Fused heterocyclic compounds as ion channel modulators

ABSTRACT

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: 
                         
wherein Z 1 , Z 2 , Z 3 , Z 4 , X, Y, R 2 , R 3  and R 4  are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/872,787, filed Oct. 1, 2015 which is a continuation of U.S.application Ser. No. 14/038,646, filed Sep. 26, 2013, now U.S. Pat. No.9,193,694, which is a continuation of U.S. application Ser. No.13/789,469, filed Mar. 7, 2013, now U.S. Pat. No. 8,697,863, which is acontinuation of U.S. application Ser. No. 13/538,847, filed Jun. 29,2012, now U.S. Pat. No. 8,586,732, which claims the benefit under 35U.S.C. §119(e) to U.S. Provisional Application Ser. No. 61/503,980,filed on Jul. 1, 2011 and 61/582,160, filed on Dec. 30, 2011, theentirety of which are incorporated herein by reference.

FIELD

The present disclosure relates to novel compounds and to their use inthe treatment of various diseases, including cardiovascular diseases anddiabetes. The disclosure also relates to methods for preparation of thecompounds and to pharmaceutical compositions comprising such compounds.

BACKGROUND

The late sodium current (INaL) is a sustained component of the fast Na+current of cardiac myocytes and neurons. Many common neurological andcardiac conditions are associated with abnormal (INaL) enhancement,which contributes to the pathogenesis of both electrical and contactiledysfunction in mammals. See, for example, Pathophysiology andPharmacology of the Cardiac “Late Sodium Current”, Pharmacology andTherapeutics 119 (2008) 326-339. Accordingly, compounds that selectivelyinhibit (INaL) in mammals are useful in treating such disease states.

One example of a selective inhibitor of (INaL) is RANEXA®, a compoundapproved by the FDA for the treatment of chronic stable angina pectoris.RANEXA® has also been shown to be useful for the treatment of a varietyof cardiovascular diseases, including ischemia-reperfusion injury,arrhythmia and unstable angina, and also for the treatment of diabetes.It would be desirable to provide novel compounds that selectivelyinhibit (INaL) in mammals and that have the similar or improvedselectivity over peak INa inhibition of the cardiac sodium channel asRANEXA®.

SUMMARY

Accordingly, typical embodiments the present disclosure provide novelcompounds that function as late sodium channel blockers. In oneembodiment, the disclosure provides compounds of Formula I:

wherein:

-   -   Z¹ and Z² are each independently selected from the group        consisting of CR⁷ and N;    -   Z³ and Z⁴ are each independently selected from the group        consisting of CR⁷, C-Q-R¹ and N, provided that one of Z³ and Z⁴        is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further        provided that only one of Z¹, Z² and Z⁴ is N;    -   X is —O— or —NR⁶—;    -   Y is —C(O)—, —C(R¹¹)₂— or —S(O)₂—;    -   Q is a covalent bond, —O—C₀₋₂ alkylene, —NR¹¹—C₀₋₂ alkylene, C₂        alkylene, C₂ alkenylene or C₂ alkynylene;    -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,            —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, aryl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, C₁₋₃ haloalkyl, cycloalkyl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH—, or        —NHC(O)—; provided that        -   when Y is —C(R¹¹)₂—, then R² is -L-R⁵, -L-C₁₋₆ alkylene-R⁵,            —C₁₋₆ alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵ and            L is not —C(O)—; and        -   when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵, then L is not —O—,            —S—, —NHS(O)₂— or —NHC(O)—;    -   each R³ is independently hydrogen, deuterium, C₁₋₆ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰,            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when Y is —C(O)—, then R² and one of R³ can join together        with the atom to which they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₆ alkyl,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰,            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and            -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                heterocyclyl, heteroaryl, are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁶ is hydrogen, C₁₋₆ alkyl or cycloalkyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁷ is hydrogen, halo, —O—R²⁰ or C₁₋₆ alkyl;    -   R¹¹ is hydrogen or C₁₋₄ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and        -   wherein said heteroaryl is optionally further substituted            with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof;    -   provided that when Y is —C(O)—, X is —O—, each R⁴ is hydrogen,        R² and R³ together with the atom to which they are attached form        a piperazine which is optionally substituted with        tert-butoxycarbonyl and Q is a bond, then R¹ is not        unsubstituted phenyl or morpholinyl; and that when Y is —S(O)₂—,        X is —O—, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is        a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

In certain embodiments, the disclosure provides compounds of Formula IA:

wherein:

-   -   Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;    -   Q is a covalent bond, —O—C₀₋₂ alkylene, —NR¹¹—C₀₋₂ alkylene, C₂        alkylene, C₂ alkenylene or C₂ alkynylene;    -   m is 0, 1, 2 or 3;    -   n is 0, 1, 2, 3, 4 or 5;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—; provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—; and    -   each R³ is independently hydrogen, deuterium, C₁₋₆ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₆ alkyl,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰,            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰,    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R¹⁷ is halo, —O—R²⁰ or C₁₋₆ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof;    -   provided that when each R⁴ is hydrogen, R² and R³ together with        the atom to which they are attached form a piperazine which is        optionally substituted with tert-butoxycarbonyl, Q is a bond and        Cy is phenyl or morpholinyl, then n is 1, 2, 3, 4 or 5.

Some embodiments provide a method of using the compounds of Formula I,IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII orXIII, or additional Formula(s) described throughout, in the treatment ofa disease or condition in a mammal that is amenable to treatment by alate sodium channel blocker. Such diseases include cardiovasculardiseases such as atrial and ventricular arrhythmias, heart failure(including congestive heart failure, diastolic heart failure, systolicheart failure, acute heart failure), Prinzmetal's (variant) angina,stable and unstable angina, exercise induced angina, congestive heartdisease, ischemia, recurrent ischemia, reperfusion injury, myocardialinfarction, acute coronary syndrome, peripheral arterial disease andintermittent claudication. Such diseases may also include diabetes andconditions related to diabetes, e.g. diabetic peripheral neuropathy.Such diseases may also include conditions affecting the neuromuscularsystem resulting in pain, seizures or paralysis. Therefore, it iscontemplated that the compounds of the disclosure and theirpharmaceutically acceptable salt, ester, stereoisomer, mixture ofstereoisomers and/or tautomer forms are potentially of use asmedicaments for the treatment of the aforementioned diseases.

In certain embodiments, the disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the disclosure (e.g. a compound of Formula I or additional Formulasdescribed throughout), and at least one pharmaceutically acceptableexcipient.

In certain embodiments, the compound is:

-   4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-1);-   4-(2-(pyrrolidin-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-3);-   4-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-4);-   4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-5);-   4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-7);-   (R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-8);-   4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-10);-   (S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-12);-   (R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-13);-   6-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)picolinonitrile    (II-14);-   7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-15);-   7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-16);-   4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-17);-   (2R,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one    (II-21);-   (R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-22);-   (R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-23);-   (S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-24);-   (S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-25);-   4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-31);-   4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-33);-   7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-35);-   tert-butyl    (2R,11aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11a-hexahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ylcarbamate    (II-39);-   4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-41);-   4-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-42);-   ethyl    3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)benzoate    (II-43);-   4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-44);-   4-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-45);-   4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-47);-   4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-48);-   4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-49);-   4-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-50);-   (2S,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one    (II-51);-   4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-54);-   4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-57);-   (R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one    (II-59);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-61);-   4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-62);-   4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-64);-   4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-65);-   4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-67);-   4-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-68);-   4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-69);-   4-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-70);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-72);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-73);-   4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-75);-   (R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-83);-   4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-87);-   7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-88);-   7-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-89);-   7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-91);-   7-(4-cyclopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one (II-92);-   (R)-4-(1-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-95);-   7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one (II-97);-   7-(4-tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-98);-   7-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-102);-   7-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-104);-   7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-105);-   7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-106);-   4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-107);-   7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-110);-   7-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-113);-   7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-115);-   7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-117);-   1-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl)cyclopentanecarbonitrile    (II-122);-   7-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-123);-   7-(4-(difluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-124);-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-129);-   4-((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-133);-   4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-134);-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-135);-   7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-136);-   4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-137);-   4-(4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-138);-   4-((4-(piperidin-1-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-139);-   4-((4-(dimethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-140);-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-141);-   4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-143);-   7-(4-(cyclobutylmethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-144);-   7-(2-methyl-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-145);-   7-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-146);-   4-((1-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-147);-   7-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-148);-   4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-150);-   4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-151);-   4-((1-cyclopentyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-152);-   4-((1-ethyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-153);-   4-((1-methyl-1H-imidazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-154);-   4-((4-methyl-1H-pyrazol-1-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-155);-   4-((4-chloro-1H-pyrazol-1-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-156);-   7-(4-(difluoromethyl)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-157);-   7-(4-chloro-3-fluorophenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-158);-   7-(4-(difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-159);-   4-((1-methyl-1H-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-160);-   4-(pyrimidin-2-ylmethyl)-7-(2,3,4-trifluorophenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-162);-   7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one (II-163);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-164);-   4-benzyl-9-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-165);-   4-benzyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-166);-   4-benzyl-8-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-167);-   4-benzyl-8-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-168);-   7-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-169);-   7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-fluoropyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-170);-   4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl    trifluoromethanesulfonate (II-171);-   4-((5-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-172);-   2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-174);-   4-((6-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-175);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-176);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide    (II-177);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)cyclopropanesulfonamide    (II-179);-   4-((1-methyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-186);-   4-((1-benzyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-187);-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-189);-   N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propane-1-sulfonamide    (II-190);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)pyrimidine-2-carboxamide    (II-192);-   7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-193);-   7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-194);-   7-(3-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-195);-   7-(4-tert-butylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (V-1);-   7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (V-3);-   7-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (V-5);-   7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-4);-   7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-12);-   4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-26);-   7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-30);-   4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-31);-   7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-32);-   7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-36); and-   4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-37);-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-4);-   7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one-   (VIII-5);-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-6);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-7);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-8);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-9);-   (E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-10); and-   4-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-11);-   2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone    (IX-2);-   2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone    (IX-3);-   4-(2-(benzyloxy)ethyl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione    (X-7);-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione    (X-8);-   4-benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione    (X-11);-   5-benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-6(5H)-one    (X-12);-   4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-1);-   4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one    (XII-2);-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one    (XII-3);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-5);-   4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-8);-   4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-9);-   4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-10);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-11);-   4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-14);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-1);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-2);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-3);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-4);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-6); or-   7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-10);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In other embodiments, the compound is:

-   4-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-6);-   4-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-11);-   (R)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-19);-   4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-46);-   (S)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-77);-   3-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-142);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)ethanesulfonamide    (II-178); or-   4-(3-(azetidin-1-ylsulfonyl)propyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-191);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In other embodiments, the compound is:

-   pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-1);-   phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-4);-   (1-methylcyclopropyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-10);-   (3,3-difluorocyclobutyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-11);-   (1-methyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-12);-   (1H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-15);-   pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-23);-   pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-24);-   2-(pyridin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone    (III-29);-   2-(pyrimidin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone    (III-30);-   (1-methyl-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-32);-   (1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,    3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (III-33);-   (1-methyl-1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,    3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (III-37);-   (R)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)(pyrimidin-2-yl)methanone    (III-38);-   tert-butyl    2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate    (III-40);-   (1H-1,2,4-triazol-3-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-50); or-   (1,5-dimethyl-1H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-58);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

The inventions of this disclosure are described throughout. In addition,specific embodiments of the invention are as disclosed herein.

DETAILED DESCRIPTION 1. Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (in some embodiments, 1, 2 or 3 substituents)        selected from the group consisting of alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl,        acylamino, acyloxy, amino, substituted amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl,        —S(O)-cycloalkyl, —S(O)— heterocyclyl, —S(O)-aryl,        —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,        —S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless        otherwise constrained by the definition, all substituents may        optionally be further substituted by 1, 2 or 3 substituents        chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and        —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and        n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from        oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents), as defined for substituted alkyl or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as definedfor substituted alkyl or a lower alkyl group as defined above that hasboth 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4 or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, in some embodiments, having 1,2, 3, 4, 5 or 6 carbon atoms.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl. This term is exemplified by groupssuch as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,t-butoxy, n-hexyloxy, and the like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl or —Y—Z, in which Y is substituted alkylene and Z issubstituted alkenyl or substituted alkynyl, where substituted alkyl,substituted alkenyl and substituted alkynyl are as defined herein.

The term “C₁₋₃ haloalkyl” refers to an alkyl group having from 1 to 3carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1to 3, halogen(s), where alkyl and halogen are defined herein. In someembodiments, C₁₋₃ haloalkyl includes, by way of example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, 2-fluoroethyl, 3,3,3-trifluoropropyl,3,3-difluoropropyl, 3-fluoropropyl.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. The term “substituted cycloalkyl”also includes cycloalkyl groups wherein one or more of the annularcarbon atoms of the cycloalkyl group has an oxo group bonded thereto. Inaddition, a substituent on the cycloalkyl or cycloalkenyl may beattached to the same carbon atom as, or is geminal to, the attachment ofthe substituted cycloalkyl or cycloalkenyl to the 6,7-ring system.Unless otherwise constrained by the definition, all substituents mayoptionally be further substituted by 1, 2 or 3 substituents chosen fromalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “substituted cycloalkoxy” refers to the group substitutedcycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “substituted cycloalkenyloxy” refers to the group substitutedcycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)— cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring. In some embodiments, the heterocyclyl,”“heterocycle,” or “heterocyclic” group is linked to the remainder of themolecule through one of the heteroatoms within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. In addition, a substituent on theheterocyclic group may be attached to the same carbon atom as, or isgeminal to, the attachment of the substituted heterocyclic group to the6,7-ring system. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examplesof heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, andthe like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine.

The term “partially saturated heteroaryl” refers to a heteroaryl havinga structure equivalent to an underlying aromatic heteroaryl which hashad one or more double bonds in an aromatic ring of the underlyingaromatic heteroaryl saturated. Examples of partially saturatedheteroaryls include dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy,amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridylor furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazoleor benzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone”refers to a group —S(O)₂R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

A compound of a given formula (e.g. the compound of Formula I, whichalso includes Formula IA, IB, II, IIA, III, IIIA, IV, V, VI, VIII,VIIIA, IX, X, XI and XIII) is intended to encompass the compounds of thedisclosure, and the pharmaceutically acceptable salts, pharmaceuticallyacceptable esters, isomers, tautomers, solvates, isotopes, hydrates,polymorphs, and prodrugs of such compounds. Additionally, the compoundsof the disclosure may possess one or more asymmetric centers, and can beproduced as a racemic mixture or as individual enantiomers ordiastereoisomers. The number of stereoisomers present in any givencompound of a given formula depends upon the number of asymmetriccenters present (there are 2^(n) stereoisomers possible where n is thenumber of asymmetric centers). The individual stereoisomers may beobtained by resolving a racemic or non-racemic mixture of anintermediate at some appropriate stage of the synthesis or by resolutionof the compound by conventional means. The individual stereoisomers(including individual enantiomers and diastereoisomers) as well asracemic and non-racemic mixtures of stereoisomers are encompassed withinthe scope of the present disclosure, all of which are intended to bedepicted by the structures of this specification unless otherwisespecifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

Some of the compounds exist as tautomeric isomers. Tautomeric isomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.Non-limiting examples of amide-comprising and imidic acid-comprisingtautomers are shown below:

The term “therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending upon the subject and disease condition beingtreated, the weight and age of the subject, the severity of the diseasecondition, the manner of administration and the like, which can readilybe determined by one of ordinary skill in the art.

The term “polymorph” refers to different crystal structures of acrystalline compound. The different polymorphs may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism).

The term “solvate” refers to a complex formed by the combining of acompound of Formula I, IA, IB, II, IIA, BB, III, IIIA, IV, V, VI, VIII,VIIIA, IX, X, XII or XIII and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound of Formula I, IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII,VIIIA, IX, X, XII or XIII and water.

The term “prodrug” refers to compounds of Formula I, IA, IB, II, IIA,IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII that includechemical groups which, in vivo, can be converted and/or can be split offfrom the remainder of the molecule to provide for the active drug, apharmaceutically acceptable salt thereof or a biologically activemetabolite thereof.

Any formula or structure given herein, including Formula I, IA, IB, II,IIA, BB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIIIcompounds, is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the disclosure include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but notlimited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F,³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopically labeled compounds ofthe present disclosure, for example those into which radioactiveisotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopicallylabelled compounds may be useful in metabolic studies, reaction kineticstudies, detection or imaging techniques, such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)including drug or substrate tissue distribution assays or in radioactivetreatment of patients.

The disclosure also included compounds of Formula I, IA, IB, II, IIA,IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII in which from1 to n hydrogens attached to a carbon atom is/are replaced by deuterium,in which n is the number of hydrogens in the molecule. Such compoundsexhibit increased resistance to metabolism and are thus useful forincreasing the half life of any compound of Formula I when administeredto a mammal. See, for example, Foster, “Deuterium Isotope Effects inStudies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527(1984). Such compounds are synthesized by means well known in the art,for example by employing starting materials in which one or morehydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

The term “treatment” or “treating” means administration of a compound ofthe invention, by or at the direction of a competent caregiver, to amammal having a disease for purposes including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group. Amines are of general structure N(R³⁰)(R³¹)(R³²),wherein mono-substituted amines have 2 of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substituted amines have 1 ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen,whereas tri-substituted amines have none of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ and R³² are selectedfrom a variety of substituents such as hydrogen, optionally substitutedalkyl, aryl, heteroayl, cycloalkyl, cycloalkenyl, heterocyclyl and thelike. The above-mentioned amines refer to the compounds wherein eitherone, two or three substituents on the nitrogen are as listed in thename. For example, the term “cycloalkenyl amine” refers tocycloalkenyl-NH₂, wherein “cycloalkenyl” is as defined herein. The term“diheteroarylamine” refers to NH(heteroaryl)₂, wherein “heteroaryl” isas defined herein and so on.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Coronary diseases” or “cardiovascular diseases” refer to diseases ofthe cardiovasculature arising from any one or more than one of, forexample, heart failure (including congestive heart failure, diastolicheart failure and systolic heart failure), acute heart failure,ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina(including exercise-induced angina, variant angina, stable angina,unstable angina), acute coronary syndrome, diabetes and intermittentclaudication.

“Intermittent claudication” means the pain associated with peripheralartery disease. “Peripheral artery disease” or PAD is a type ofocclusive peripheral vascular disease (PVD). PAD affects the arteriesoutside the heart and brain. The most common symptom of PAD is a painfulcramping in the hips, thighs or calves when walking, climbing stairs orexercising. The pain is called intermittent claudication. When listingthe symptom intermittent claudication, it is intended to include bothPAD and PVD.

Arrhythmia refers to any abnormal heart rate. Bradycardia refers toabnormally slow heart rate whereas tachycardia refers to an abnormallyrapid heart rate. As used herein, the treatment of arrhythmia isintended to include the treatment of supra ventricular tachycardias suchas atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia,atrial tachycardia and the ventricular tachycardias (VTs), includingidiopathic ventricular tachycardia, ventricular fibrillation,pre-excitation syndrome and Torsade de Pointes (TdP).

2. Nomenclature

Names of compounds of the present disclosure are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto, Canada). Other compounds or radicals may be named withcommon names or systematic or non-systematic names. The naming andnumbering of the compounds of the disclosure is illustrated with arepresentative compound of Formula I:

which is named4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

3. Compounds

Accordingly, typical embodiments the present disclosure provide novelcompounds that function as late sodium channel blockers. In oneembodiment, the disclosure provides compounds of Formula I:

wherein:

-   -   Z¹ and Z² are each independently selected from the group        consisting of CR⁷ and N;    -   Z³ and Z⁴ are each independently selected from the group        consisting of CR⁷, C-Q-R¹ and N, provided that one of Z³ and Z⁴        is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further        provided that only one of Z¹, Z² and Z⁴ is N;    -   X is —O— or —NR⁶—;    -   Y is —C(O)—, —C(R¹¹)₂— or —S(O)₂—;    -   Q is a covalent bond, —O—C₀₋₂ alkylene, —NR¹¹—C₀₋₂ alkylene, C₂        alkylene, C₂ alkenylene or C₂ alkynylene;    -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),            —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶,            —S(O)₂—R²⁰, —O—S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl,            C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and            heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, aryl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, C₁₋₃ haloalkyl, cycloalkyl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH—, or        —NHC(O)—; provided that        -   when Y is —C(R¹¹)₂—, then R² is -L-R⁵, -L-C₁₋₆ alkylene-R⁵,            —C₁₋₆ alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵ and            L is not —C(O)—; and        -   when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵, then L is not —O—,            —S—, —NHS(O)₂— or —NHC(O)—;    -   each R³ is independently hydrogen, deuterium, C₁₋₆ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when Y is —C(O)—, then R² and one of R³ can join together        with the atom to which they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₆ alkyl,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁶ is hydrogen, C₁₋₆ alkyl or cycloalkyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁷ is hydrogen, halo, —O—R²⁰ or C₁₋₆ alkyl;    -   R¹¹ is hydrogen or C₁₋₄ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof;    -   provided that when Y is —C(O)—, X is —O—, each R⁴ is hydrogen,        R² and R³ together with the atom to which they are attached form        a piperazine which is optionally substituted with        tert-butoxycarbonyl and Q is a bond, then R¹ is not        unsubstituted phenyl or morpholinyl; and that when Y is —S(O)₂—,        X is —O—, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is        a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

In another embodiment, the disclosure provides compounds of Formula I:

wherein:

-   -   Z¹ and Z² are each independently selected from the group        consisting of CR⁷ and N; Z³ and Z⁴ are each independently        selected from the group consisting of CR⁷, C-Q-R¹ and N,        provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and        Z⁴ is CR⁷ or N and further provided that only one of Z² and Z⁴        is N;    -   X is —O— or —NR⁶—;    -   Y is —C(O)—;    -   Q is a covalent bond, —O—C₀₋₂ alkylene, —NR¹¹—C₀₋₂ alkylene, C₂        alkylene, C₂ alkenylene or C₂ alkynylene;    -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two, three,            four or five substituents independently selected from the            group consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃,            —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,            —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—; provided that        -   when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵, then L is not —O—,            —S—, —NHS(O)₂— or —NHC(O)—; and    -   each R³ is independently hydrogen, deuterium, C₁₋₆ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₆ alkyl,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁶ is hydrogen, C₁₋₆ alkyl or cycloalkyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁷ is hydrogen, halo, —O—R²⁰ or C₁₋₆ alkyl;    -   R¹¹ is hydrogen or C₁₋₄ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof;    -   provided that when X is —O—, each R⁴ is hydrogen, R² and R³        together with the atom to which they are attached form a        piperazine which is optionally substituted with        tert-butoxycarbonyl and Q is a bond, then R¹ is not        unsubstituted phenyl or morpholinyl.

In another embodiment, the disclosure provides compounds of Formula I:

-   -   wherein Z¹, Z², Z³, Z⁴, X, R³ and R⁴ are as defined herein;    -   Y is —C(R¹¹)₂—;    -   R² is -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵ or —C₁₋₆        alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or —NHC(O)—; and    -   R¹¹ is hydrogen or C₁₋₄ alkyl.

In yet another embodiment, the disclosure provides compounds of FormulaI:

-   -   wherein Z¹, Z², Z³, Z⁴, X, R², R³ and R⁴ are as defined herein;        and    -   Y is —S(O)₂—;    -   provided that when X is —O—, R² is benzyl, each R³ is hydrogen,        Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then        both R⁴ are hydrogen.

In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl;

-   -   wherein said aryl, cycloalkenyl or heteroaryl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —O—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,        —S(O)₂—R²⁰, —O—S(O)₂—R²⁰, C₁₋₆ alkyl, cycloalkyl and        heterocyclyl; and        -   wherein said C₁₋₆ alkyl or cycloalkyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —CN and —O—R²⁰.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₆ alkyl.

In some embodiments, each R⁴ is independently hydrogen, deuterium orC₁₋₆ alkyl.

In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of C₁₋₆ alkyl,        halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),        —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or            heteroaryl are optionally further substituted with one, two            or three substituents independently selected from the group            consisting of halo, C₁₋₆ alkyl, aryl, heterocyclyl and            heteroaryl; and            -   wherein said C₁₋₆ alkyl is optionally further                substituted with one, two or three halo.

In some embodiments, R² and one of R³ can join together with the atom towhich they are attached to form a heterocyclyl;

-   -   wherein said heterocyclyl is optionally substituted with one,        two or three substituents independently selected from the group        consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²) and —C(O)—OR²⁰;        and        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo and heteroaryl.

In certain embodiments of each of the formulas disclosed herein, each—C₁₋₆ alkylene of R² is unsubstituted —C₁₋₆ alkylene.

In certain embodiments, the compound is not tert-butyl6-oxo-8-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(6H)-carboxylate,tert-butyl6-oxo-9-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(6H)-carboxylate,8-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one,9-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one,8-morpholino-1,2,3,4,12,12a-hexahydrobenzo[e]pyrazino[1,2-a]azepin-6(11H)-one,tert-butyl8-morpholino-6-oxo-3,4,6,11,12,12a-hexahydrobenzo[e]pyrazino[1,2-a]azepine-2(1H)-carboxylate,tert-butyl2-morpholino-12-oxo-5,6,6a,7,9,10-hexahydropyrazino[1,2-a]pyrido[3,2-e]azepine-8(12H)-carboxylate,2-morpholino-6,6a,7,8,9,10-hexahydropyrazino[1,2-a]pyrido[3,2-e]azepin-12(5H)-one,2-morpholino-8,9,10,10a,11,12-hexahydropyrazino[1,2-a]pyrido[2,3-e]azepin-5(7H)-oneor tert-butyl2-morpholino-5-oxo-7,8,10,10a,11,12-hexahydropyrazino[1,2-a]pyrido[2,3-e]azepine-9(5H)-carboxylate.

In alternative embodiments, the disclosure provides compounds of FormulaI:

wherein:

-   -   Z¹ and Z² are each independently selected from the group        consisting of CR⁷ and N;    -   Z³ and Z⁴ are each independently selected from the group        consisting of CR⁷, C-Q-R¹ and N, provided that one of Z³ and Z⁴        is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further        provided that only one of Z¹, Z² and Z⁴ is N;    -   X is —O— or —NR⁶—;    -   Y is —C(O)—, —C(R¹¹)₂— or —S(O)₂—;    -   Q is a covalent bond, —O—C₀₋₂ alkylene, —NR¹¹—C₀₋₂ alkylene or        C₂ alkynylene;    -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,            —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, phenyl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²),                —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵ or        —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—; provided that        -   when Y is —C(R¹¹)₂—, then R² is -L-R⁵, alkylene-R⁵, —C₁₋₆            alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   each R³ is independently hydrogen, deuterium, C₁₋₁₅ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or when Y is —C(O)—, then R² and one of R³ can join together        with the atom to which they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₁₅ alkyl, C₁₋₄        alkoxy, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(O)₂—R²⁰,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—OR²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁶ is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁷ is hydrogen, halo or C₁₋₆ alkyl;    -   R¹¹ is hydrogen or C₁₋₄ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof;    -   provided that when Y is —C(O)—, X is —O—, each R⁴ is hydrogen,        R² and R³ together with the atom to which they are attached form        a piperazine which is optionally substituted with        tert-butoxycarbonyl and Q is a bond, then R¹ is not        unsubstituted phenyl or morpholinyl; and that when Y is —S(O)₂—,        X is —O—, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is        a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl;

-   -   wherein said aryl, cycloalkenyl or heteroaryl are optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, —O—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,        —S(O)₂—R²⁰, —O—S(O)₂—R²⁰, C₁₋₆ alkyl, cycloalkyl and        heterocyclyl; and        -   wherein said C₁₋₆ alkyl or cycloalkyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —CN and —O—R²⁰.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₁₅ alkyl.

In some embodiments, each R⁴ is independently hydrogen, deuterium orC₁₋₁₅ alkyl.

In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of C₁₋₆ alkyl,        halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),        —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or            heteroaryl are optionally further substituted with one, two            or three substituents independently selected from the group            consisting of halo, C₁₋₆ alkyl, aryl, heterocyclyl and            heteroaryl; and            -   wherein said C₁₋₆ alkyl is optionally further                substituted with one, two or three halo.

In some embodiments, Y is —C(O)— and R² and one of R³ can join togetherwith the atom to which they are attached to form a heterocyclyl;

-   -   wherein said heterocyclyl is optionally substituted with one,        two or three substituents independently selected from the group        consisting of C₁₋₁₅ alkyl, —O—R²⁰, —N(R²⁰)(R²²) and —C(O)—OR²⁰;        and        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo and heteroaryl.

In some embodiments, the disclosure provides compounds of Formula IA:

wherein:

-   -   Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;    -   Q is a covalent bond, —O—C₀₋₂ alkylene, —NR¹¹—C₀₋₂ alkylene, C₂        alkylene, C₂ alkenylene or C₂ alkynylene;    -   m is 0, 1, 2 or 3;    -   n is 0, 1, 2, 3, 4 or 5;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—; provided that        -   when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵, then L is not —O—,            —S—, —NHS(O)₂— or —NHC(O)—; and    -   each R³ is independently hydrogen, deuterium, C₁₋₆ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₆ alkyl,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R¹⁷ is halo, —O—R²⁰ or C₁₋₆ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof;    -   provided that when each R⁴ is hydrogen, R² and R³ together with        the atom to which they are attached form a piperazine which is        optionally substituted with tert-butoxycarbonyl, Q is a bond and        Cy is phenyl or morpholinyl, then n is 1, 2, 3, 4 or 5.

In certain embodiments, the disclosure provides compounds of Formula II:

wherein:

-   -   m is 0, 1, 2 or 3;    -   n is 0, 1, 2, 3, 4 or 5;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   each R³ is independently hydrogen, deuterium, C₁₋₆ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₆ alkyl,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R¹⁷ is halo, —O—R²⁰ or C₁₋₆ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof;    -   provided that when m is 0, each R⁴ is hydrogen, R² and R³        together with the atom to which they are attached form a        piperazine which is optionally substituted with        tert-butoxycarbonyl and Q is a bond, then n is 1, 2 or 3.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵ or —C₁₋₆ alkylene-L-R⁵.

In some embodiments, each —C₁₋₆ alkylene of R² is optionally substitutedby one substituent independently selected from the group consisting ofC₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,heteroaryl or heterocyclyl; and

-   -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of C₁₋₆ alkyl,        C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl, aryl, heterocyclyl,        heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,        —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of C₁₋₆ alkyl,        halo, cycloalkyl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),        —C(O)—OR²⁰, —CN and —O—R²⁰;        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally further            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl and aryl; and            -   wherein said C₁₋₆ alkyl is optionally further                substituted with one, two or three halo.

In some embodiments, R² and one of R³ can join together with the atom towhich they are attached to form a heterocyclyl;

-   -   wherein said heterocyclyl is optionally substituted with one,        two or three substituents independently selected from the group        consisting of C₁₋₆ alkyl, —O—R²⁰, —N(R²⁰)(R²²) and —C(O)—OR²⁰;        and        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo and heteroaryl.

In some embodiments, R² is

or R² and one of R³ together with the carbon atoms to which they areattached form a

In some embodiments, n is 1, 2 or 3; and

-   -   each R¹⁰ is independently selected from the group consisting of        halo, —O—R²⁰, —O—S(O)₂—R²⁰, C₁₋₄ alkyl and cycloalkyl; and        -   wherein said alkyl and cycloalkyl are optionally substituted            with one, two or three halo or —CN; and    -   R²⁰ is independently selected from the group consisting of C₁₋₆        alkyl, cycloalkyl and aryl; and        -   wherein the alkyl and aryl are optionally substituted with            one, two or three halo or cycloalkyl.

In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl,4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trifluoromethyl,4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4-trifluoromethoxy,4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyl,4-(2,2,2-trifluoroethyl), 4-cyclopropoxy, 4-cyclobutylmethoxy,4-fluorophenoxy, 4-phenoxy or 3-phenoxy.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₆ alkyl optionally substituted with heteroaryl;

or R² and one of R³ can join together with the atom to which they areattached to form a heterocyclyl;

-   -   wherein said heterocyclyl is optionally substituted with one,        two or three substituents independently selected from the group        consisting of C₁₋₆ alkyl, —N(R²⁰)(R²²) and —N(R²⁰)—C(O)—OR²⁰;        and        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo and heteroaryl; and    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl and heteroaryl.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₆ alkyl optionally substituted with heteroaryl; and

each R⁴ is independently hydrogen, deuterium or C₁₋₆ alkyl optionallysubstituted with heteroaryl.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₆ alkyl optionally substituted with heteroaryl;

m is 0 or 1; and

R¹⁷ is halo.

In some embodiments, each R³ is independently hydrogen, deuterium,methyl, isopropyl or pyridin-2-ylmethyl;

m is 0 or 1; and

R¹⁷ is fluoro.

In some embodiments, each R⁴ is independently hydrogen, deuterium orC₁₋₆ alkyl.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₆ alkyl optionally substituted with heteroaryl;

-   -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₆ alkyl, —N(R²⁰)(R²²) and            —N(R²⁰)—C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl; and    -   each R⁴ is independently hydrogen, deuterium or C₁₋₆ alkyl        optionally substituted with heteroaryl.

In certain embodiments, the disclosure provides compounds of FormulaIIA:

wherein:

-   -   n is 0, 1, 2 or 3;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   each R³ is independently hydrogen or C₁₋₆ alkyl;    -   each R⁴ is independently hydrogen or C₁₋₆ alkyl;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of FormulaIIB:

wherein:

-   -   n is 0, 1, 2 or 3;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl;        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            —N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²²,            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),) CN, oxo and            —O—R²⁰; and            -   wherein said C₁₋₆ alkyl is optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃ and —C(O)—NH₂; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃ and —OCF₃; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In some embodiments, n is 1, 2 or 3; and

-   -   each R¹⁰ is independently selected from the group consisting of        halo, —O—R²⁰, —O—S(O)₂—R²⁰, C₁₋₄ alkyl and cycloalkyl; and        -   wherein said alkyl and cycloalkyl are optionally substituted            with one, two or three halo or —CN; and    -   R²⁰ is C₁₋₆ alkyl, cycloalkyl or aryl; and        -   wherein the alkyl and aryl are optionally substituted with            one, two or three halo or cycloalkyl.

In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl,4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trifluoromethyl,4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4-trifluoromethoxy,4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyl,4-(2,2,2-trifluoroethyl), 4-cyclopropoxy, 4-cyclobutylmethoxy,4-fluorophenoxy, 4-phenoxy or 3-phenoxy.

In some embodiments, the compound is selected from the group consistingof:

-   4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-1);-   4-(2-(pyrrolidin-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-3);-   4-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-4);-   4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-5);-   4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-7);-   (R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-8);-   4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-10);-   (S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-12);-   (R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-13);-   6-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)picolinonitrile    (II-14);-   7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-15);-   7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-16);-   4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-17);-   (2R,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one    (II-21);-   (R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-22);-   (R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-23);-   (S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-24);-   (S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-25);-   4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-31);-   4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-33);-   7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-35);-   tert-butyl    (2R,11aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11a-hexahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ylcarbamate    (II-39);-   4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-41);-   4-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-42);-   ethyl    3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)benzoate    (II-43);-   4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-44);-   4-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-45);-   4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-47);-   4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-48);-   4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-49);-   4-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-50);-   (2S,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one    (II-51);-   4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-54);-   4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-57);-   (R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one    (II-59);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-61);-   4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-62);-   4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-64);-   4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-65);-   4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-67);-   4-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-68);-   4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-69);-   4-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-70);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-72);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-73);-   4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-75);-   (R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one    (II-83);-   4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-87);-   7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-88);-   7-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-89);-   7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-91);-   7-(4-cyclopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one (II-92);-   (R)-4-(1-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-95);-   7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one (II-97);-   7-(4-tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-98);-   7-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-102);-   7-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-104);-   7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-105);-   7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-106);-   4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-107);-   7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-110);-   7-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-113);-   7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-115);-   7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-117);-   1-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl)cyclopentanecarbonitrile    (II-122);-   7-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-123);-   7-(4-(difluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-124);-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-129);-   4-(4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-133);-   4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-134);-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-135);-   7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-136);-   4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-137);-   4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-138);-   4-((4-(piperidin-1-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-139);-   4-((4-(dimethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-140);-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-141);-   4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-143);-   7-(4-(cyclobutylmethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-144);-   7-(2-methyl-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-145);-   7-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-146);-   4-((1-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-147);-   7-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-148);-   4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-150);-   4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-151);-   4-((1-cyclopentyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-152);-   4-((1-ethyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-153);-   4-((1-methyl-1H-imidazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-154);-   4-((4-methyl-1H-pyrazol-1-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-155);-   4-((4-chloro-1H-pyrazol-1-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-156);-   7-(4-(difluoromethyl)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-157);-   7-(4-chloro-3-fluorophenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-158);-   7-(4-(difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-159);-   4-((1-methyl-1H-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-160);-   4-(pyrimidin-2-ylmethyl)-7-(2,3,4-trifluorophenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-162);-   7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one (II-163);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-164);-   4-benzyl-9-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-165);-   4-benzyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-166);-   4-benzyl-8-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-167);-   4-benzyl-8-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-168);-   7-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-169);-   7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-170);-   4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl    trifluoromethanesulfonate (II-171);-   4-((5-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-172);-   2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-174);-   4-((6-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-175);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-176);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide    (II-177);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)cyclopropanesulfonamide    (II-179);-   4-((1-methyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-186);-   4-(1-benzyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-187);-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-189);-   N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propane-1-sulfonamide    (II-190);-   N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)pyrimidine-2-carboxamide    (II-192);-   7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-193);-   7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-194); and-   7-(3-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (II-195);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula II:

wherein:

-   -   m is 0 or 1;    -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   each R³ is independently hydrogen, deuterium, C₁₋₁₅ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₁₅ alkyl, C₁₋₄        alkoxy, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(O)₂—R²⁰,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²)(R²²), —S(O)₂—R²⁰ and —O—R²⁰;    -   R¹⁷ is halo or C₁₋₆ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof;    -   provided the compound is not tert-butyl        6-oxo-8-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(6H)-carboxylate,        tert-butyl        6-oxo-9-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,        1-c][1,4]oxazepine-2(6H)-carboxylate,        8-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one,        or        9-phenyl-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵ or —C₁₋₆ alkylene-L-R⁵.

In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of C₁₋₆ alkyl,        halo, cycloalkyl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),        —C(O)—OR²⁰, —CN and —O—R²⁰;        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally further            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl and aryl; and            -   wherein said C₁₋₆ alkyl is optionally further                substituted with one, two or three halo.

In some embodiments, R² and one of R³ can join together with the atom towhich they are attached to form a heterocyclyl;

-   -   wherein said heterocyclyl is optionally substituted with one,        two or three substituents independently selected from the group        consisting of C₁₋₁₅ alkyl, —O—R²⁰, —N(R²⁰)(R²²) and —C(O)—OR²⁰;        and        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo and heteroaryl.

In some embodiments, R² is

orR² and one of R³ together with the carbon atoms to which they areattached form a

In some embodiments, n is 1, 2 or 3; and

-   -   each R¹⁰ is independently selected from the group consisting of        halo, —O—R²⁰, —O—S(O)₂—R²⁰, C₁₋₄ alkyl and cycloalkyl; and        -   wherein said alkyl is optionally substituted with one, two            or three halo; and    -   R²⁰ is independently selected from the group consisting of        C₁-C₁₅ alkyl and cycloalkyl; and        -   wherein the alkyl is optionally substituted with one, two or            three halo or cycloalkyl.

In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl,4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trifluoromethyl,4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4-trifluoromethoxy,4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyl,4-(2,2,2-trifluoroethyl), 4-cyclopropoxy or 4-cyclobutylmethoxy.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₁₅ alkyl optionally substituted with heteroaryl;

-   -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —N(R²⁰)(R²²) and            —N(R²⁰)—C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl; and    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl and heteroaryl.

In some embodiments, each R³ is independently hydrogen, deuterium orC₁₋₁₅ alkyl optionally substituted with heteroaryl.

In some embodiments, each R³ is independently hydrogen, deuterium,methyl, isopropyl or pyridin-2-ylmethyl.

In some embodiments, each R⁴ is independently hydrogen, deuterium orC₁₋₁₅ alkyl.

In some embodiments, each R⁴ is independently hydrogen, deuterium ormethyl.

In some embodiments, m is 0.

In some embodiments, m is 1; and R¹⁷ is halo.

In some embodiments, m is 1; and R¹⁷ is fluoro.

In certain embodiments, the disclosure provides compounds of FormulaIII:

wherein:

-   -   n is 0, 1, 2, 3, 4 or 5:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵ or —C₁₋₆        alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or —NHC(O)—,        provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵, then L is        not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   each R³ is independently hydrogen, deuterium, C₁₋₁₅ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₁₅ alkyl, C₁₋₄        alkoxy, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(O)₂—R²⁰,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula III:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵ or —C₁₋₆        alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   each R³ is independently hydrogen, deuterium, C₁₋₁₅ alkyl,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₁₅ alkyl, C₁₋₄        alkoxy, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(O)₂—R²⁰,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is —C(O)—R⁵ or —C(O)—C₁₋₆ alkylene-R⁵; and

-   -   R⁵ is cycloalkyl, aryl or heteroaryl;    -   wherein said cycloalkyl or heteroaryl are optionally substituted        with one, two or three substituents independently selected from        the group consisting of C₁₋₆ alkyl, halo and —C(O)—OR²⁰.

In some embodiments, R⁵ is cycloalkyl, aryl or heteroaryl;

-   -   wherein said cycloalkyl or heteroaryl are optionally substituted        with one, two or three substituents independently selected from        the group consisting of C₁₋₆ alkyl, halo and —C(O)—OR²⁰.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is

In some embodiments, n is 1; and

-   -   R¹⁰ is —O—R²⁰ or C₁₋₄ alkyl;    -   wherein said alkyl is optionally substituted with one, two or        three halo; and    -   R²⁰ is C₁-C₁₅ alkyl;    -   wherein the alkyl is optionally substituted with one, two or        three halo.

In some embodiments, n is 1; and R¹⁰ is 4-trifluoromethyl or4-trifluoromethoxy.

In some embodiments, the compound is selected from the group consistingof:

-   pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-1);-   phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-4);-   (1-methylcyclopropyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-10);-   (3,3-difluorocyclobutyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-11);-   (1-methyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-12);-   (1H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-15);-   pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-23);-   pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-24);-   2-(pyridin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone    (III-29);-   2-(pyrimidin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone    (III-30);-   (1-methyl-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-32);-   (1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,    3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (III-33);-   (1-methyl-1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,    3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (III-37);-   (R)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)(pyrimidin-2-yl)methanone    (III-38);-   tert-butyl    2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate    (III-40);-   (1H-1,2,4-triazol-3-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-50); and-   (1,5-dimethyl-1H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    (III-58);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of Formula IV:

wherein:

-   -   n is 0, 1, 2, 3, 4 or 5:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            wherein said heteroaryl is optionally further substituted            with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula IV:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   S(O)R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In certain embodiments, the disclosure provides compounds of Formula V:

wherein:

-   -   A is cycloalkenyl;    -   n is 0, 1, 2, 3, 4 or 5;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula V:

wherein:

-   -   A is cycloalkenyl;    -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O— S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵.

In some embodiments, R⁵ is heteroaryl.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is

In some embodiments, A is cyclohex-1-enyl.

In some embodiments, A is cyclohex-1-enyl; n is 0 or 1; and R¹⁰ is4-methyl or 4-tert-butyl.

In some embodiments, the compound is selected from the group consistingof:

-   7-(4-tert-butylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (V-1);-   7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (V-3); and-   7-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (V-5);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of Formula VI:

wherein:

-   -   B is heterocyclyl or heteroaryl;    -   n is 0, 1, 2, 3, 4 or 5:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula VI:

wherein:

-   -   B is heterocyclyl or heteroaryl;    -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, B is heteroaryl.

In some embodiments, B is 2-oxo-1,2-dihydropyridin-4-yl, pyridin-4-yl,pyridin-2-yl, thiazol-4-yl or thiophen-2-yl.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵.

In some embodiments, R⁵ is heteroaryl.

In some embodiments, R² is

In some embodiments, n is 1;

R¹⁰ is cycloalkyl, —O—R²⁰ or C₁₋₄ alkyl;

wherein said alkyl is optionally substituted with one, two or threehalo; and

R²⁰ is C₁-C₁₅ alkyl.

In some embodiments, n is 1;

R¹⁰ is —O—R²⁰ or C₁₋₄ alkyl;

wherein said alkyl is optionally substituted with one, two or threehalo; and

R²⁰ is C₁-C₁₅ alkyl.

In some embodiments, B is 2-oxo-1,2-dihydropyridin-4-yl, pyridin-4-yl,5-(trifluoromethyl)pyridin-2-yl, 2-isopropylthiazol-4-yl,5-(trifluoromethyl)thiophen-2-yl or 5-cyclopropylthiophen-2-yl.

In some embodiments, the compound is selected from the group consistingof:

-   7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-4);-   7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-12);-   4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-26);-   7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-30);-   4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-31);-   7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-32);-   7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-36); and-   4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VI-37);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of FormulaVIII:

wherein:

-   -   n is 0, 1, 2, 3, 4 or 5;    -   represents a single, double or triple bond;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is

In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or4-trifluoromethoxy.

In some embodiments, the compound is selected from the group consistingof:

-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-4);-   7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-5);-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-6);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-7);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-8);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-9);-   (E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-10); and-   4-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-11);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of FormulaVIIIA:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵.

In some embodiments, R⁵ is heteroaryl.

In some embodiments, R² is

In some embodiments, n is 0 or 1;

R¹⁰ is —O—R²⁰ or C₁₋₄ alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is C₁₅ alkyl; and

wherein the alkyl is optionally substituted with one, two or three halo.

In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or4-trifluoromethoxy.

In some embodiments, the compound is selected from the group consistingof:

-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-4);-   7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-5); and-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (VIII-6);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of Formula IX:

wherein:

-   -   n is 0, 1, 2, 3, 4 or 5;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula IX:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;            or a pharmaceutically acceptable salt, ester, hydrate,            solvate, stereoisomer, mixture of stereoisomers, tautomer,            polymorph and/or prodrug thereof.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵.

In some embodiments, R² is not benzyl.

In some embodiments, R⁵ is heteroaryl;

-   -   wherein said heteroaryl is optionally further substituted with        halo.

In some embodiments, R² is selected from the group consisting of

In some embodiments, R¹⁰ is 4-trifluoromethyl.

In some embodiments, the compound is selected from the group consistingof:

-   2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone    (IX-2); and-   2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone    (IX-3);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of Formula X:

wherein:

-   -   n is 0, 1, 2, 3, 4 or 5;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₁₅ alkyl, C₁₋₄        alkoxy, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(O)₂—R²⁰,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R⁴ together with the carbon atom to which they are        attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁶ is hydrogen, C₁₋₆ alkyl or cycloalkyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula X:

wherein:

-   -   n is 0, 1, 2 or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   each R⁴ is independently hydrogen, deuterium, C₁₋₁₅ alkyl, C₁₋₄        alkoxy, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(O)₂—R²⁰,        cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R⁴ together with the carbon atom to which they are        attached form an oxo;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁶ is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵.

In some embodiments, R⁵ is aryl.

In some embodiments, R² is

In some embodiments, R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

In some embodiments, each R⁴ is independently hydrogen, deuterium orC₁₋₆ alkyl optionally substituted with heteroaryl, or two R⁴ togetherwith the carbon atom to which they are attached form an oxo.

In some embodiments, two R⁴ together with the carbon atom to which theyare attached form an oxo.

In some embodiments, R⁶ is hydrogen or C₁₋₆ alkyl.

In some embodiments, R⁶ is hydrogen or methyl.

In some embodiments, the compound is selected from the group consistingof:

-   4-(2-(benzyloxy)ethyl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione    (X-7);-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione    (X-8);-   4-benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione    (X-11); and-   5-benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-6(5H)-one    (X-12);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of FormulaXII:

wherein:

-   -   Z¹ and Z² are each independently selected from the group        consisting of CR⁷ and N;    -   Z⁴ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;    -   n is 0, 1, 2, 3, 4 or 5;    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁷ is hydrogen, halo or C₁₋₆ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula XII:

wherein:

-   -   Z¹ and Z² are each independently selected from the group        consisting of CR⁷ and N;    -   Z⁴ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;    -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁷ is hydrogen, halo or C₁₋₆ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆alkylene-R⁵.

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R⁵ is cycloalkyl, aryl or heteroaryl;

-   -   wherein said heteroaryl is optionally substituted with one, two        or three substituents independently selected from the group        consisting of C₁₋₆ alkyl, halo and —O—R²⁰.

In some embodiments, R² is

In some embodiments, n is 0 or 1;

R¹⁰ is —O—R²⁰ or C₁₋₄ alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is C₁-C₁₅ alkyl; and

wherein the alkyl is optionally substituted with one, two or three halo.

In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or4-trifluoromethoxy.

In some embodiments, the compound is selected from the group consistingof:

-   4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-1);-   4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one    (XII-2);-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one    (XII-3);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-5);-   4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-8);-   4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-9);-   4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-10);-   4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-11); and-   4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one    (XII-14);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain embodiments, the disclosure provides compounds of FormulaXIII:

wherein:

-   -   Q is a —O—C₀₋₂ alkylene- or —NR¹¹—C₀₋₂ alkylene-;    -   n is 1, 2, 3, 4 or 5;    -   R¹⁰ is halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —N(R²⁰)—C(O)—OR²²,        —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²),        C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl,        heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, C₁₋₃            haloalkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, -L-C₁₋₆ alkylene-R⁵, —C₁₋₆        alkylene-L-R⁵ or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;        -   wherein each —C₁₋₆ alkylene is optionally substituted by one            substituent independently selected from the group consisting            of C₂₋₄ alkynyl, halo, —NO₂, —CN, —O—R²⁰, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁰)(R²²), —N(R²⁰)—S(O)₂—R²⁰,            cycloalkyl, aryl, heteroaryl or heterocyclyl; and            -   wherein said cycloalkyl, aryl, heteroaryl or                heterocyclyl are optionally substituted with one, two or                three substituents independently selected from the group                consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—, provided that when R² is -L-R⁵ or -L-C₁₋₆ alkylene-R⁵,        then L is not —O—, —S—, —NHS(O)₂— or —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R¹¹ is hydrogen or C₁₋₄ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, stereoisomer,        mixture of stereoisomers or tautomer thereof.

In other embodiments, the disclosure provides compounds of Formula XIII:

wherein:

-   -   Q is a —O—C₀₋₂ alkylene- or —NR¹¹—C₀₋₂ alkylene-;    -   n is 1, 2 or 3;    -   R¹⁰ is halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —C(O)—OR²², —N(R²⁰)—S(O)₂—        R²⁶, —S(O)₂—R²⁰, —O—S(O)₂—R²⁰, —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is —C₁₋₆ alkylene-R⁵, -L-R⁵, alkylene-R⁵, —C₁₋₆ alkylene-L-R⁵        or —C₁₋₆ alkylene-L-C₁₋₆ alkylene-R⁵;    -   L is —O—, —S—, —C(O)—, —NHS(O)₂—, —S(O)₂NH—, —C(O)NH— or        —NHC(O)—;    -   R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl            are optionally substituted with one, two or three            substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —N(R²⁰)—S(O)₂—R²⁰, —N(R²⁰)—C(O)—R²², —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, aryl, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R¹¹ is hydrogen or C₁₋₄ alkyl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —S(O)₂R²⁶,            —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, Q is a —O—, —NH— or —NR¹¹—.

In some embodiments, R¹¹ is methyl

In some embodiments, each —C₁₋₆ alkylene of R² is unsubstituted.

In some embodiments, R² is —C₁₋₆ alkylene-R⁵.

In some embodiments, R⁵ is heteroaryl.

In some embodiments, R² is

In some embodiments, n is 1;

R¹⁰ is —O—R²⁰;

R²⁰ is C₁-C₁₅ alkyl; and

wherein the alkyl is optionally substituted with one, two or three halo.

In some embodiments, R¹⁰ is 4-trifluoromethoxy.

In some embodiments, the compound is selected from the group consistingof:

-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-1);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-2);-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-3);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-4);-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-6); and-   7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one    (XIII-10);    or a pharmaceutically acceptable salt, ester, stereoisomer, mixture    of stereoisomers or tautomer thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula IB:

wherein:

-   -   R¹ is aryl, cycloalkenyl, heterocyclyl or heteroaryl;    -   wherein said aryl, cycloalkenyl, heterocyclyl or heteroaryl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of halo, —NO₂,        —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰,        —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   Q is a covalent bond or C₂ alkynylene;    -   Y is —C(O)—, —CH₂—, —C(NR⁵)— or —S(O)₂—;    -   X is —O— or —NR⁶—;    -   each R³ is independently hydrogen, C₁₋₁₅ alkyl, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ or two R⁴ together with the carbon atom to which they        are attached form an oxo;    -   R⁵ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and R⁵ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of C₁₋₁₅            alkyl, cycloalkyl, heteroaryl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   R⁶ is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In certain alternative embodiments, when Y is —C(O)—, X is —O—, each R⁴is hydrogen, R² and R³ together with the atom to which they are attachedform a piperazine which is optionally substituted withtert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenylor morpholinyl; and that when Y is —S(O)₂—, X is —O—, R² is benzyl, eachR³ is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl,then both R⁴ are hydrogen.

In certain alternative embodiments, the disclosure provides compounds ofFormula IIA:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)²—R²⁰ and                    —O—R²⁰;    -   each R³ is independently hydrogen, C₁₋₁₅ alkyl, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   each R⁴ is independently hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is hydrogen or C₁₋₁₅ alkyl;

-   -   wherein said alkyl is optionally substituted with one, two or        three substituents independently selected from the group        consisting of halo, aryl, heterocyclyl, heteroaryl, cycloalkyl        and —O—R²⁰;        -   wherein said aryl, heterocyclyl or heteroaryl are optionally            further substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, heterocyclyl, heteroaryl, cycloalkyl,            —C(O)—OR²⁰, —CN and —O—R²⁰; and            -   wherein said C₁₋₆ alkyl, or heteroaryl are optionally                further substituted with one, two or three substituents                independently selected from the group consisting of halo                and —CF₃;    -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —N(R²⁰)(R²²) and            —N(R²⁰)—C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl; and    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl and heteroaryl.

In some embodiments, R² is hydrogen,

R² and one of R³ together with the carbon atoms to which they areattached form a

or a pharmaceutically acceptable salt, ester, hydrate, solvate,stereoisomer, mixture of stereoisomers, tautomer, polymorph and/orprodrug thereof.

In some embodiments, n is 1 or 2; and

-   -   each R¹⁰ is independently selected from the group consisting of        halo, —O—R²⁰, C₁₋₄ alkyl and cycloalkyl; and        -   wherein said alkyl is optionally substituted with one, two            or three halo; and    -   R²⁰ is independently selected from the group consisting of        C₁-C₁₅ alkyl and cycloalkyl; and        -   wherein the alkyl is optionally substituted with one, two or            three halo.

In some embodiments, n is 1 or 2; and each R¹⁰ is independently selectedfrom the group consisting of 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro,4-chloro, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-trifluoromethyl,4-cyclopropyl, 4-isobutoxy, 4-trifluoromethoxy,4-(2,2,2-trifluoroethoxy) and 4-cyclopropoxy.

In some embodiments, each R³ is independently hydrogen or C₁₋₁₅ alkyl;

-   -   or R² and one of R³ can join together with the atom to which        they are attached to form a heterocyclyl;        -   wherein said heterocyclyl is optionally substituted with            one, two or three substituents independently selected from            the group consisting of C₁₋₁₅ alkyl, —N(R²⁰)(R²²) and            —N(R²⁰)—C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl; and    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁-C₁₅ alkyl and heteroaryl.

In some embodiments, each R³ is independently hydrogen or C₁₋₁₅ alkyl.

In some embodiments, each R³ is independently hydrogen, methyl orisopropyl.

In some embodiments, the compound is selected from the group consistingof

-   4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2-(pyrrolidin-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   (R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one;-   4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   4-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   (S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   (R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   6-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)picolinonitrile;-   7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   (R)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   (2R,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one;-   (R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one;-   (R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one;-   (S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,    1-c][1,4]oxazepin-6(2H)-one;-   (S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,    1-c][1,4]oxazepin-6(2H)-one;-   4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,    5,5-trimethyl-1,3-dioxan-2-yl)ethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   tert-butyl    (2R,11aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11a-hexahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ylcarbamate;-   4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((4,    6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   ethyl    3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)benzoate;-   4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2,    6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   (2    S,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one;-   4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   (R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one;-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   (S)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   (R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one;-   4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-cyclopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   (R)-4-(1-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;    and-   4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula IIIA:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is —C(O)—R²⁰; and

R²⁰ is heteroaryl.

In some embodiments, R² is

In some embodiments, n is 1; and

R¹⁰ is —O—R²⁰; and

R²⁰ is C₁-C₁₅ alkyl; and

-   -   wherein the alkyl is optionally substituted with one, two or        three halo.

In some embodiments, n is 1; and R¹⁰ is 4-trifluoromethoxy.

In some embodiments, the compound is

-   pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula IV:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula V:

wherein:

-   -   A is cycloalkenyl;    -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, A is cyclohex-1-enyl.

In some embodiments, R² is C₁₋₁₅ alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

In some embodiments, R² is

In some embodiments, n is 0 or 1; and

R¹⁰ is C₁₋₄ alkyl.

In some embodiments, A is cyclohex-1-enyl;

n is 0 or 1; and

R¹⁰ is 4-methyl or 4-tert-butyl.

In some embodiments, the compound is selected from the group consistingof

-   7-(4-tert-butylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;-   7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;    and-   7-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula VI:

wherein:

-   -   B is heterocyclyl or heteroaryl;    -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, —CF₃,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, B is heterocyclyl.

In some embodiments, B is 2-oxo-1,2-dihydropyridin-4-yl.

In some embodiments, B is heteroaryl.

In some embodiments, B is pyridin-4-yl.

In some embodiments, R² is C₁₋₁₅ alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

In some embodiments, R² is

In some embodiments, n is 1;

R¹⁰ is —O—R²⁰ or C₁₋₄ alkyl; and

R²⁰ is C₁-C₁₅ alkyl.

In some embodiments, B is 2-tert-butoxypyridin-4-yl.

In some embodiments, B is 1-methyl-2-oxo-1,2-dihydropyridin-4-yl.

In some embodiments, the compound is selected from the group consistingof

-   7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;    and-   7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula VIIIA:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or            heteroaryl are optionally further substituted with one, two            or three substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, —CF₃,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —S(O)₂—R²⁰ and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;            or a pharmaceutically acceptable salt, ester, hydrate,            solvate, stereoisomer, mixture of stereoisomers, tautomer,            polymorph and/or prodrug thereof.

In some embodiments, R² is C₁₋₁₅ alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

In some embodiments, R² is

In some embodiments, n is 0 or 1;

R¹⁰ is —O—R²⁰ or C₁₋₄ alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is C₁-C₁₅ alkyl; and

wherein the alkyl is optionally substituted with one, two or three halo.

In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or4-trifluoromethoxy.

In some embodiments, the compound is selected from the group consistingof

-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;-   7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;    and-   4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5    (2H)-one;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula IX:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²)—C(O)—OR²², —N(R²⁰)— S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰; —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —S(O)₂—R²⁰ and                    —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is C₁₋₁₅ alkyl;

-   -   wherein said alkyl is optionally substituted with heteroaryl;        and

wherein said heteroaryl is optionally further substituted with halo.

In some embodiments, R² is selected from the group consisting of

In some embodiments, R¹⁰ is 4-trifluoromethyl.

In some embodiments, the compound is selected from the group consistingof:

-   2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone;    and-   2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In certain alternative embodiments, the disclosure provides compounds ofFormula X:

wherein:

-   -   n is 0, 1, 2 or 3;    -   R¹⁰ is independently selected from the group consisting of halo,        —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(O)₂—R²⁶, —S(O)₂—R²⁰,        —S(O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, —S(O)₂—R²⁰ and                    —O—R²⁰;    -   each R⁴ is independently hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy,        —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(O)₂—R²⁰, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl, heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R⁴ together with the carbon atom to which they are        attached form an oxo;    -   R⁶ is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶, cycloalkyl,        aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —S(O)₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl; and            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, R² is C₁₋₁₅ alkyl;

wherein the alkyl is optionally substituted with aryl or —O—R²⁰; and

R²⁰ is C₁-C₁₅ alkyl;

wherein the alkyl is optionally substituted with aryl.

In some embodiments, R² is

In some embodiments, R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

In some embodiments, two R⁴ together with the carbon atom to which theyare attached form an oxo.

In some embodiments, R⁶ is hydrogen or C₁₋₁₅ alkyl.

In some embodiments, R⁶ is hydrogen or methyl.

In some embodiments, the compound is selected from the group consistingof

-   4-(2-(benzyloxy)ethyl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione;    and-   4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

In some embodiments of Formula I and each of the other formulasdisclosed herein, R²⁰ and R²² are in each instance independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,        heterocyclyl, aryl and heteroaryl are optionally substituted        with one, two or three substituents independently selected from        the group consisting of hydroxyl, halo, C₁₋₄ alkyl, acylamino,        —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃,        —C(O)—NH₂, aryl, cycloalkyl and heteroaryl; and        -   wherein said heteroaryl is optionally further substituted            with C₁₋₄ alkyl or cycloalkyl; or            when R²⁰ and R²² are attached to a common nitrogen atom R²⁰            and R²² may join to form a heterocyclic or heteroaryl ring            which is then optionally substituted with one, two or three            substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, aralkyl, aryl,            aryloxy, aralkyloxy, acylamino, —NO₂, —S(O)₂R²⁶, —CN, C₁₋₃            alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and cycloalkyl.

In certain embodiments, R²⁰ is hydrogen or C₁₋₆ alkyl; wherein the C₁₋₆alkyl is optionally substituted with one, two or three halo.

In certain embodiments, R²⁰ is hydrogen. In other embodiments, R²⁰ is—CF₃.

4. Further Embodiments

In some embodiments, the compounds provided by the present disclosureare effective in the treatment of conditions or diseases known torespond to administration of late sodium channel blockers, including butnot limited to cardiovascular diseases such as atrial and ventriculararrhythmias, including atrial fibrillation, Prinzmetal's (variant)angina, stable angina, unstable angina, ischemia and reperfusion injuryin cardiac, kidney, liver and the brain, exercise induced angina,pulmonary hypertension, congestive heart disease including diastolic andsystolic heart failure, and myocardial infarction. In some embodiments,compounds provided by the present disclosure which function as latesodium channel blockers may be used in the treatment of diseasesaffecting the neuromuscular system resulting in pain, itching, seizures,or paralysis, or in the treatment of diabetes or reduced insulinsensitivity, and disease states related to diabetes, such as diabeticperipheral neuropathy.

Certain compounds of the disclosure may also possess a sufficientactivity in modulating neuronal sodium channels, i.e., Na_(v), 1.1, 1.2,1.3, 1.5, 1.7, and/or 1.8, and may have appropriate pharmacokineticproperties such that they may be active with regard to the centraland/or peripheral nervous system. Consequently, some compounds of thedisclosure may also be of use in the treatment of epilepsy or pain oritching or heachache of a neuropathic origin.

In one embodiment, this disclosure provides a method of treating adisease state in a mammal that is alleviable by treatment with an agentcapable of reducing late sodium current, comprising administering to amammal in need thereof a therapeutically effective dose of a compound ofFormula I, IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX,X, XII or XIII or other formulas or compounds disclosed herein. Inanother embodiment, the disease state is a cardiovascular diseaseselected from one or more of atrial and ventricular arrhythmias, heartfailure (including congestive heart failure, diastolic heart failure,systolic heart failure, acute heart failure), Prinzmetal's (variant)angina, stable and unstable angina, exercise induced angina, congestiveheart disease, ischemia, recurrent ischemia, reperfusion injury,myocardial infarction, acute coronary syndrome, peripheral arterialdisease, pulmonary hypertension, and intermittent claudication.

In another embodiment, the disease state is diabetes or diabeticperipheral neuropathy. In a further embodiment, the disease stateresults in one or more of neuropathic pain, epilepsy, heachache,seizures, or paralysis.

In one embodiment, this disclosure provides a method of treatingdiabetes in a mammal, comprising administering to a mammal in needthereof a therapeutically effective dose of a compound of Formula I, IA,IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIIIor other formulas or compounds disclosed herein. Diabetes mellitus is adisease characterized by hyperglycemia; altered metabolism of lipids,carbohydrates and proteins; and an increased risk of complications fromvascular disease. Diabetes is an increasing public health problem, as itis associated with both increasing age and obesity.

There are two major types of diabetes mellitus: 1) Type I, also known asinsulin dependent diabetes (IDDM) and 2) Type II, also known as insulinindependent or non-insulin dependent diabetes (NIDDM). Both types ofdiabetes mellitus are due to insufficient amounts of circulating insulinand/or a decrease in the response of peripheral tissue to insulin.

Type I diabetes results from the body's failure to produce insulin, thehormone that “unlocks” the cells of the body, allowing glucose to enterand fuel them. The complications of Type I diabetes include heartdisease and stroke; retinopathy (eye disease); kidney disease(nephropathy); neuropathy (nerve damage); as well as maintenance of goodskin, foot and oral health.

Type II diabetes results from the body's inability to either produceenough insulin or the cells inability to use the insulin that isnaturally produced by the body. The condition where the body is not ableto optimally use insulin is called insulin resistance. Type II diabetesis often accompanied by high blood pressure and this may contribute toheart disease. In patients with type II diabetes mellitus, stress,infection, and medications (such as corticosteroids) can also lead toseverely elevated blood sugar levels. Accompanied by dehydration, severeblood sugar elevation in patients with type II diabetes can lead to anincrease in blood osmolality (hyperosmolar state). This condition canlead to coma.

It has been suggested that ranolazine (RANEXA®, a selective inhibitor ofINaL) may be an antidiabetic agent that causes β-cell preservation andenhances insulin secretion in a glucose-dependent manner in diabeticmice (see, Y. Ning et al. J Pharmacol Exp Ther. 2011, 337(1), 50-8).Therefore it is contemplated that the compounds of Formula I, IA, IB,II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII orother formulas or compounds disclosed herein can be used as antidiabeticagents for the treatment of diabetes.

5. Pharmaceutical Compositions and Administration

Compounds provided in accordance with the present disclosure are usuallyadministered in the form of pharmaceutical compositions. This disclosuretherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present disclosure. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present disclosure in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. Preferably, for parenteral administration, sterileinjectable solutions are prepared containing a therapeutically effectiveamount, e.g., 0.1 to 700 mg, of a compound described herein. It will beunderstood, however, that the amount of the compound actuallyadministered usually will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Oral administration is another route for administration of compounds inaccordance with the disclosure. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present disclosure employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present disclosure incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g, or alternatively, or 100 mg to 500 mg, of a compounddescribed herein, and for parenteral administration, preferably from 0.1mg to 700 mg, or alternatively, 0.1 mg to 100 mg, of a compound acompound described herein. It will be understood, however, that theamount of the compound actually administered usually will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound administered and its relative activity, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present disclosure may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

Combination Therapy

Patients being treated by administration of the late sodium channelblockers of the disclosure often exhibit diseases or conditions thatbenefit from treatment with other therapeutic agents. These diseases orconditions can be of cardiovascular nature or can be related topulmonary disorders, metabolic disorders, gastrointestinal disorders andthe like. Additionally, some coronary patients being treated byadministration of the late sodium channel blockers of the disclosureexhibit conditions that can benefit from treatment with therapeuticagents that are antibiotics, analgesics, and/or antidepressants andanti-anxiety agents.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the late sodium channel blockers of thedisclosure with other therapeutic agents include, without limitation,angina including stable angina, unstable angina (UA), exercised-inducedangina, variant angina, arrhythmias, intermittent claudication,myocardial infarction including non-STE myocardial infarction (NSTEMI),pulmonary hypertension including pulmonary arterial hypertension, heartfailure including congestive (or chronic) heart failure and diastolicheart failure and heart failure with preserved ejection fraction(diastolic dysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the late sodium channel blockers of thedisclosure with therapeutic agents suitable for treating cardiovascularrelated conditions allows enhancement in the standard of care therapythe patient is currently receiving. In some embodiments, the late sodiumchannel blockers of the disclosure are co-administered with ranolazine(RANEXA®).

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral®),atenolol (Tenormin®), betaxolol (Kerlone®),bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol(Cartrol®), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®),metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol(Inderal®), sotalol (Betapace®), and timolol (Blocadren®).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc®, Lotrel®),bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine(Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®),nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), andnicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Bumex®),spironolactone (Aldactone®), and eplerenone (Inspra®).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin®),captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®),lisinopril Zestril®), moexipril (Univasc®), perindopril (Aceon®),quinapril (Accupril®), ramipril (Altace®), and trandolapril (Mavik®).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantinesulfinpyrazone, dipyridamole, indomethacin, and glycoprotein 11b/111ainhibitors, such as abciximab, tirofiban, and eptifibatide(Integrelin®). Beta blockers and calcium channel blockers also have aplatelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interest(see U.S. Patent Application Publication No. 2010/0056536 and U.S.Patent Application Publication No. 2011/0183990, the entirety of whichare incorporated herein).

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot formation.Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress®), doxazosin mesylate(Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide(Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergicantagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol(Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride(Catapres®), clonidine hydrochloride and chlorthalidone (Clorpres®,Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochloride(Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide(Aldoclor®), methyldopa and hydrochlorothiazide (Aldoril®); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne®,Trandate®), carvedilol (Coreg®); adrenergic neuron blocking agents, suchas guanethidine (Ismelin®), reserpine (Serpasil®); central nervoussystem-acting antihypertensives, such as clonidine (Catapres®),methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin IIagents; ACE inhibitors, such as perindopril (Aceon®) captopril(Capoten®), enalapril (Vasotec®), lisinopril Zestril®); angiotensin-IIreceptor antagonists, such as candesartan (Atacand®), eprosartan(Teveten®), irbesartan (Avapro®), losartan (Cozaar®), telmisartan(Micardis®), valsartan (Diovan®); calcium channel blockers, such asverapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifedipine(Adalat®, Procardia®); diuretics; direct vasodilators, such asnitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine(Apresoline®), minoxidil (Loniten®), verapamil; and potassium channelactivators, such as aprikalim, bimakalim, cromakalim, emakalim,nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins,such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin(Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®)pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin(Zocor®).

In this disclosure, the patient presenting with an acute coronarydisease event often suffers from secondary medical conditions such asone or more of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient a compound as disclosed herein (e.g., Formula I, IA, IB,II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII) incombination with at least one therapeutic agent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol (Proventir),salmeterol (Serevent®, Serevent Diskus®), theophylline, ipratropiumbromide (Atrovent®), tiotropium (Spiriva®), methylprednisolone(Solu-Medrol®, Medrol®), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix®),lansoprazole (Prevacid®), esomeprazole (Nexium®), omeprazole(Prilosec®), rabeprazole; H2 blockers, such as cimetidine (Tagamet®),ranitidine (Zantac®), famotidine (Pepcid®), nizatidine (Axid®);prostaglandins, such as misoprostol (Cytotec®); sucralfate; andantacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with a compound as disclosed herein (e.g., FormulaI, IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XIIor XIII).

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include β-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime,cefadroxil) (Duricef®), cephalexin (Keflex®), cephradine (Velosef®),cefaclor (Ceclor®), cefuroxime axtel (Ceftin®), cefprozil (Cefzil®),loracarbef (Lorabid®), cefixime (Suprax®), cefpodoxime proxetil(Vantin®), ceftibuten (Cedax®), cefdinir (Omnicef®), ceftriaxone(Rocephin®), carbapenems, and monobactams; tetracyclines, such astetracycline; macrolide antibiotics, such as erythromycin;aminoglycosides, such as gentamicin, tobramycin, amikacin; quinolonessuch as ciprofloxacin; cyclic peptides, such as vancomycin,streptogramins, polymyxins; lincosamides, such as clindamycin;oxazolidinoes, such as linezolid; and sulfa antibiotics, such assulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the late sodium channel blockers of the disclosure totreat neuropathic pain via inhibition of the Na_(V) 1.7 and 1.8 sodiumchannels, combination with analgesics are particularly invisioned. SeeU.S. Patent Application Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillers. Examples of antidepressant and anti-anxiety agents includebenzodiazepines, such as diazepam, lorazepam, and midazolam;enzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft®, Lustral®, Apo-Sertral®, Asentra®,Gladem®, Serlift®, Stimuloton®; escitalopram (Lexapro®, Cipralex®);fluoxetine (Prozac® Sarafem® Fluctin® Fontex®, Prodep®, Fludep®,Lovan®); venlafaxine (Effexor® XR, Efexor®); citalopram (Celexa®,Cipramil®, Talohexane®); paroxetine (Paxil®, Seroxat®, Aropax®);trazodone (Desyrel®); amitriptyline (Elavil®); and bupropion(Wellbutrin®, Zyban®).

Accordingly, one aspect of the disclosure provides for a compositioncomprising the late sodium channel blockers of the disclosure and atleast one therapeutic agent. In an alternative embodiment, thecomposition comprises the late sodium channel blockers of the disclosureand at least two therapeutic agents. In further alternative embodiments,the composition comprises the late sodium channel blockers of thedisclosure and at least three therapeutic agents, the late sodiumchannel blockers of the disclosure and at least four therapeutic agents,or the late sodium channel blockers of the disclosure and at least fivetherapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the late sodium channel blockers of thedisclosure and therapeutic agent or agents, essentially contemporaneousadministration of more than one formulation comprising the late sodiumchannel blocker of the disclosure and therapeutic agent or agents, andconsecutive administration of a late sodium channel blocker of thedisclosure and therapeutic agent or agents, in any order, whereinpreferably there is a time period where the late sodium channel blockerof the disclosure and therapeutic agent or agents simultaneously exerttheir therapeutic affect.

6. Synthesis of Example Compounds

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more of Formula I,IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII orXIII or other formulas or compounds disclosed herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers.

General Syntheses

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

The compounds of Formula I (and Formula IA, IB, II, IIA, IIB, III, IIIA,IV, V, VI, VIII, VIIIA, IX, X, XII or XIII) are typically prepared byfirst providing the molecular core 1-1 and then attaching the desired-Q-R¹ substituents using suitable coupling conditions (e.g., Suzukicoupling) and the desired —R² substituents using suitable substitutionconditions. These processes are show below in Scheme 1 for the synthesisof a compound of Formula I, wherein -Q-R¹ is at either Z³ or Z⁴ in eachof Formulas 1-1, 1-2, 1-3 and I shown in Scheme 1, wherein the bromoand/or -Q-R¹ is at either Z³ or Z⁴ in each of the Formulas shown inScheme 1.

In general, a halogenated compound of formula 1-1, in this case abrominated compound, is reacted with an appropriately substitutedboronic acid derivative of formula R¹Q-B(OH)₂ or a boronic esterthereof, in an inert solvent, for example aqueous N,N-dimethylformamide,in the presence of a mild base, for example potassium carbonate orsodium bicarbonate. The reaction is typically conducted in the presenceof a metal catalyst with an appropriate ligand, for exampledichlorobis(triphenylphosphine) palladium(II), at a temperature of about120-170° C., for about 10 minutes to about 1 hour or at a lowertemperature, i.e., 90-110° C. for 2 to 5 days. When the reaction issubstantially complete, the product of Formula I is isolated byconventional means.

It will be appreciated that the R² substitutent can be modified or addedeither before (as shown in Scheme 1) or after the addition of the R¹moiety. The R² moiety may be coupled to the core 1-1 under substitutionreaction conditions with an appropriate reagent of formula LG-R² (whereLG is a leaving group such as a halo, hydroxyl, alkoxy or the like) asshown in Scheme 1. Typical substitution reaction conditions include thepresence of a base, such as ssium carbonate, sodium bicarbonate,triethylamine, and the like, in a polar aprotic solvent, such asN,N-dimethylformamide, and optionally an elevated temperature of about100-150° C. or in a microwave. Also, in the case where the R²substituent contains a heteroaryl ring, the heteroaryl ring may besynthesized and cyclized before or after addition of the -Q-R¹ portion.

Optional Core Synthesis

In certain embodiments, the core may be synthesized before or afteraddition of the -Q-R¹ substitutent (Scheme 2). For example, suchalternative routes for the synthesis of3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one compounds of Formula 2-8(i.e., Formula IA, II, IIA, IIB, IV, V, VI VIII, X, XII and XIII) areshown in Scheme 2, below, wherein the bromo and/or -Q-R¹ is at either Z³or Z⁴ in each of the Formulas shown in Scheme 2.

In one embodiment, compounds of Formula 2-3 can be provided fromcompounds of Formula 2-1 via amide formation with a suitably protected2-2, where PG is a protecting group, such as benzyl. Compounds ofFormula 2-3 are coupled with an appropriately substituted boronic acidderivative of formula R¹Q-B(OH)₂ or a boronic ester thereof, undertypical coupling reaction conditions. Typical coupling reactionconditions an inert solvent, for example aqueous N,N-dimethylformamide,in the presence of a mild base, for example potassium carbonate orsodium bicarbonate. The reaction is typically conducted in the presenceof a metal catalyst with an appropriate ligand, for exampledichlorobis(triphenylphosphine) palladium(II), at a temperature of about120-170° C., for about 10 minutes to about 1 hour or at a lowertemperature, i.e., 90-110° C. for 2 to 5 days. When the reaction issubstantially complete, the compounds of Formula 2-4 can be isolated byconventional means. Compounds of Formula 2-4 are cyclized to affordcompounds of Formula 2-5 using sodium hydride, in a suitable solvent,such as dimethylformamide. Deprotection under suitable conditionsprovides compounds of Formula 2-6.

In another embodiment, compounds of Formula 2-8 are prepared fromcommercially available compounds of Formula 2-7 using sodium azide.Compounds of Formula 2-6 can be obtained from compounds of Formula 2-8via reaction with an appropriately substituted boronic acid derivativeof formula R¹Q-B(OH)₂ or a boronic ester thereof, under typical couplingreaction conditions as described above.

The R² moiety may be coupled to compounds of Formula 2-6 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy orthe like) as shown in Scheme 1 to afford3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one compounds of Formula 2-9.Typical substitution reaction conditions include the presence of a base,such as ssium carbonate, sodium bicarbonate, triethylamine, and thelike, in a polar aprotic solvent, such as N,N-dimethylformamide, andoptionally an elevated temperature of about 100-150° C. or in amicrowave.

2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepine compounds of Formula 3-2 (i.e.,Formula III and IIIA) are synthesized from compounds of Formula 2-6 asshown in Scheme 3, below, wherein -Q-R¹ is at either C7 or C8 in each ofthe Formulas shown in Scheme 2.

In one embodiment, compounds of Formula 3-1 can be provided from thereduction of compounds of Formula 2-6 via amide formation with asuitably protected 2-2, where PG is a protecting group, such as benzyl.The R² moiety may be coupled to compounds of Formula 2-6 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy orthe like) as shown in Scheme 1 to afford compounds of Formula 3-2.

Compounds of Formula 4-3 (i.e., Formula IX) are synthesized as shown inScheme 4, below, wherein -Q-R¹ is at either C7 or C8 in each of theFormulas shown in Scheme 2.

In one embodiment, compounds of Formula 4-3 can be provided fromcompounds of Formula 4-1 via sulfonamide formation with an amino alcohol4-2. Compounds of Formula 4-3 are coupled with an appropriatelysubstituted boronic acid derivative of formula R¹Q-B(OH)₂ or a boronicester thereof, under typical coupling reaction conditions as discussedin Scheme 2. Compounds of Formula 4-4 are cyclized to afford compoundsof Formula 5-5 using sodium hydride, in a suitable solvent, such asdimethylformamide.

The R² moiety may be coupled to compounds of Formula 4-5 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy orthe like) as shown in Scheme 1 to afford compounds of Formula 4-6.Typical substitution reaction conditions include the presence of a base,such as ssium carbonate, sodium bicarbonate, triethylamine, and thelike, in a polar aprotic solvent, such as N,N-dimethylformamide, andoptionally an elevated temperature of about 100-150° C. or in amicrowave.

It will also be appreciated that the addition of any substituent mayresult in the production of a number of isomeric products any or all ofwhich may be isolated and purified using conventional techniques.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the disclosure, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe disclosure.

List of abbreviations and acronyms. Abbreviation Meaning ° C. DegreeCelcius anal Analytical ATP Adenosine-5′-triphosphate ATX II Anemoniasulcata toxin ACN Acetonitrile CHO Chinese hamster ovary conc.Concentrated d Doublet DABCO 1,4-Diazabicyclo[2.2.2]octane dd Doublet ofdoublets DCM Dichloromethane DIPEA N,N-diisopropylethylamine DMFDimethylformamide DMSO Dimethylsulfoxide dppf1,1′-Bis(diphenylphosphino)ferrocene EA Ethyl alcohol ECF Extracellularfluid EDTA Ethylenediaminetetraacetic acid EGTA Ethylene glycoltetraacetic acid equiv/eq Equivalents ESI Electrospray ionization AcAcetate Et Ethyl g Grams HEPES(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid) HATU2-(7-Aza-1H-Benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate hERG human Ether-à-go-go Related Gene HPLCHigh-performance liquid chromatography h Hours Hz Hertz IC₅₀ The halfmaximal inhibitory concentration IMR-32 Human neuroblastoma cell line JCoupling constant Kg Kilogram kHz Kilohertz LCMS/LC-MS Liquidchromatography-mass spectrometry M Molar m multiplet m/z mass-to-chargeratio M+ Mass peak M + H Mass peak plus hydrogen Me Methyl mg MilligramMHz Megahertz min/m Minute ml/mL Milliliter mM Millimolar mmol Millimolenmol Nanomole mOsmol Milliosmole MRM Magnetic Resonance Microscopy MSMass spectroscopy ms Millisecond mV Millivolt mw Microwave N Normal molMole NMR Nuclear magnetic resonance pA Picoamps Ph Phenyl prepPreparative q.s. Quantity sufficient to achieve a stated function RfRetention factor RT/rt Room temperature s Second s Singlet SEM Standarderror of the mean t Triplet TB Tonic Block TEA Triethylamine TFATrifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatographyTTX Tetrodotoxin UDB Use Dependent Block WT Wild type δ Chemical shiftμg Microgram μL/μl Microliter μM Micromolar μm Micrometer μmol Micromole

Example 17-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-74)

Commercially available 6-bromochroman-4-one (1.0 g, 3 mmol) wasdissolved in 10 mL methanesulfonic acid. The solution was cooled usingan ice bath and sodium azide (0.30 g, 4.5 mmol) was added over a periodof 45 min. The mixture was stirred at RT for 16 h. The mixture wasneutralized using conc. HCl. The resulting solid was filtered and washedwith water to afford Compound 1-A as analytically pure sample.

For the Suzuki coupling reaction the following conditions were applied:To a suspension of Compound 1-A (1 eq), the substituted boronic acid orboronate ester (1.2 eq) and base sodium bicarbonate (3 eq) in solvent(DMF:water in the ratio of 4:1) was added palladium catalyst Pd(dppf)Cl₂(10 mol %) and heated at 80° C. for 2-4 h. The reaction progress wasfollowed by LC and after completion, the reaction mixture was filteredthrough celite, washed with ethyl acetate. The filtrate was concentratedthe filtrate and purified by prep TLC/prep HPLC or column chromatographyto afford Compound II-74.

Example 24-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-6)

Compound 2-A was prepared from Compound 1-A according to Example 1 using1-ethynyl-4-(trifluoromethyl)benzene in place of the boronic acid.

To a solution of 2-A (1 eq) in DMF was added the corresponding halide(1.3 eq). To the mixture was added sodium hydride (60% dispersion inoil, 2 mmol) and stirred at room temperature for 10 min, followed byheating at 80° C. for 24 h. The reaction mixture was quenched withwater, extracted with ethyl acetate (100 mL). The organic layer waswashed with water, brine and dried over sodium sulphate and concentratedAnd purified using prep TLC/prep HPLC or column chromatography to affordCompound VIII-6.

¹H-NMR (CDCl₃) δ 8.71 (d, 2H, J=4.4 Hz), 8.20 (d, 1H, J=2.4 Hz),7.55-7.59 (m, 5H), 7.20 (t, 1H, J=4.8 Hz), 7.01 (d, 1H, J=8.4 Hz), 5.08(s, 2H), 4.58 (t, 2H, J=4.6 Hz), 3.76 (t, 2H, J=5.0 Hz); MS m/z 424.1(M+H).

Example 34-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-72)

Compound II-72 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.81 (d, 1H, J=5.6 Hz),8.27 (t, 1H, J=7.8 Hz), 8.07 (d, 1H, J=8.4 Hz), 8.02 (d, 1H, J=2.4 Hz),7.75 (t, 1H, J=6.4 Hz), 7.65 (dd, 1H, J=8.6, 2.6 Hz), 7.58 (dd, 2H,J=4.8, 2.8 Hz), 7.28 (d, 2H, J=8.4 Hz), 7.12 (d, 1H, J=8.4 Hz), 5.24 (s,2H), 4.39 (t, 2H, J=5.0 Hz), 3.85 (t, 2H, J=5.0 Hz); MS m/z 415.1 (M+H).

Example 44-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-70)

Compound II-70 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 9.00 (s, 1H), 8.75 (d,1H, J=5.2 Hz), 8.47 (d, 1H, J=7.6 Hz), 8.05 (d, 1H, J=2.4 Hz), 7.83 (dd,1H, J=7.8, 5.4 Hz), 7.66 (dd, 1H, J=8.8, 2.4 Hz), 7.60 (d, 2H, J=8.4Hz), 7.28 (d, 2H, J=8.4 Hz), 7.13 (d, 1H, J=8.0 Hz), 4.99 (s, 2H), 4.37(t, 2H, J=5.0 Hz), 3.67 (t, 2H, J=5.0 Hz); MS m/z 415.1 (M+H).

Example 54-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-69)

Compound II-69 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.53 (d, 2H, J=4.8 Hz),8.03 (d, 1H, J=2.4 Hz), 7.58-7.61 (m, 3H), 7.27 (d, 2H, J=5.2 Hz), 7.07(d, 1H, J=8.0 Hz), 6.97 (t, 1H, J=4.8 Hz), 4.66 (t, 2H, J=4.8 Hz), 4.51(t, 2H, J=5.2 Hz), 4.07 (t, 2H, J=5.0 Hz), 3.78 (t, 2H, J=5.0 Hz); MSm/z 468.0 (M+Na).

Example 64-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-62)

Compound II-62 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.10 (d, 1H, J=2.8 Hz),7.60-7.63 (m, 3H), 7.35 (dd, 2H, J=8.4, 1.2 Hz), 7.28 (d, 2H, J=8.0 Hz),7.03-7.09 (m, 3H), 4.82 (s, 2H), 4.22 (t, 2H, J=5.2 Hz), 3.51 (t, 2H,J=5.2 Hz); MS m/z 432.1 (M+H).

Example 74-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-61)

Compound II-61 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.80 (d, 2H, J=5.2 Hz),8.19 (d, 1H, J=2.8 Hz), 7.66-7.71 (m, 5H), 7.33 (t, 1H, J=5.0 Hz), 7.13(d, 1H, J=8.4 Hz), 5.14 (s, 2H), 4.59 (t, 2H, J=4.8 Hz), 3.81 (t, 2H,J=5.0 Hz); MS m/z 400.1 (M+H).

Example 84-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-57)

Compound II-57 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.07 (d, 1H, J=2.4 Hz),7.58-7.61 (m, 3H), 7.49-7.51 (m, 1H), 7.26-7.31 (m, 3H), 7.16 (t, 1H,J=7.6 Hz), 7.07-7.18 (m, 2H), 4.92 (s, 2H), 4.29 (t, 2H, J=4.8 Hz), 3.61(t, 2H, J=5.0 Hz); MS m/z 432.1 (M+H).

Example 94-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-54)

Compound II-54 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.57 (d, 1H, J=4.8 Hz),8.03 (d, 1H, J=2.4 Hz), 7.67-7.69 (m, 1H), 7.57-7.61 (m, 3H), 7.20-7.33(m, 4H), 7.04 (d, 1H, J=8.8 Hz), 4.19 (t, 2H, J=4.8 Hz), 4.06 (t, 2H,J=7.4 Hz), 3.51 (t, 2H, J=5.0 Hz), 3.24 (t, 2H, J=6.8 Hz); MS m/z 429.1(M+H).

Example 104-(2-(1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-50)

Compound II-50 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.02 (d, 1H, J=2.4 Hz),7.58-7.64 (m, 4H), 7.47 (d, 1H, J=1.6 Hz), 7.28 (d, 2H, J=8.8 Hz), 7.04(d, 1H, J=8.4 Hz), 6.30 (t, 1H, J=2.2 Hz), 4.55 (t, 2H, J=5.8 Hz), 4.11(t, 2H, J=5.4 Hz), 3.96 (t, 2H, J=5.0 Hz), 3.28 (t, 2H, J=5.0 Hz); MSm/z 418.1 (M+H).

Example 114-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-49)

Compound II-49 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.08 (d, 1H, J=2.4 Hz),7.57-7.61 (m, 3H), 7.26-7.33 (m, 3H), 7.05 (d, 1H, J=8.4 Hz), 6.95 (t,2H, J=8.0 Hz), 4.98 (s, 2H), 4.23 (t, 2H, J=4.8 Hz), 3.59 (t, 2H, J=4.8Hz); MS m/z 450.1 (M+H).

Example 124-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-48)

Compound II-48 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.06 (d, 1H, J=2.4 Hz),7.59-7.62 (m, 3H), 7.40 (d, 2H, J=8.0 Hz), 7.25-7.29 (m, 3H), 7.06 (d,1H, J=8.4 Hz), 5.24 (s, 2H), 4.07 (t, 2H, J=5.0 Hz), 3.42 (t, 2H, J=5.2Hz); MS m/z 483.0 (M+H).

Example 134-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-47)

Compound II-47 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.10 (d, 1H, J=2.4 Hz),7.60-7.64 (m, 3H), 7.47 (dd, 1H, J=7.0, 2.2 Hz), 7.41 (dd, 1H, J=7.4,1.8 Hz), 7.26-7.30 (m, 4H), 7.09 (d, 1H, J=8.4 Hz), 5.01 (s, 2H), 4.28(t, 2H, J=5.0 Hz), 3.58 (t, 2H, J=5.2 Hz); MS m/z 448.1 (M+H).

Example 147-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-5)

Compound VIII-5 was prepared according to Example 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d, 2H, J=4.8 Hz),7.92 (d, 1H, J=2.4 Hz), 7.60 (dd, 1H, J=8.6, 1.8 Hz), 7.48-7.51 (m, 2H),7.35-7.39 (m, 4H), 7.07 (d, 1H, J=8.8 Hz), 5.05 (s, 2H), 4.59 (t, 2H,J=4.8 Hz), 3.83 (t, 2H, J=4.8 Hz); MS m/z 356.1 (M+H).

Example 154-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-4)

Compound VIII-4 was prepared according to Example 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d, 2H, J=7.2 Hz),7.95 (d, 1H, J=2.4 Hz), 7.59-7.63 (m, 3H), 7.38 (t, 1H, J=5.0 Hz), 7.29(d, 2H, J=8.4 Hz), 7.08 (d, 1H, J=8.8 Hz), 5.05 (s, 2H), 4.60 (t, 2H,J=5.0 Hz), 3.83 (t, 2H, J=4.8 Hz); MS m/z 440.1 (M+H).

Example 164-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-44)

Compound II-44 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CDCl₃) δ 8.70 (d, 2H, J=5.2 Hz),8.00 (d, 1H, J=2.4 Hz), 7.56-7.59 (m, 3H), 7.26 (d, 2H, J=8.4 Hz), 7.20(t, 1H, J=5.2 Hz), 7.04 (d, 1H, J=8.8 Hz), 4.36 (t, 2H, J=5.0 Hz), 4.16(t, 2H, J=7.0 Hz), 3.59 (t, 2H, J=5.0 Hz), 3.38 (t, 2H, J=6.0 Hz); MSm/z 430.1 (M+H).

Example 174-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-42)

Compound II-42 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.00 (d, 1H, J=2.4 Hz),7.76 (dd, 1H, J=8.2, 2.6 Hz), 7.69 (dd, 2H, J=6.8, 2.0 Hz), 7.34 (d, 2H,J=8.0 Hz), 7.16 (d, 1H, J=8.8 Hz), 6.11 (s, 1H), 4.87 (s, 2H), 4.58 (t,2H, J=5.0 Hz), 3.93 (s, 6H), 3.84 (t, 2H, J=5.2 Hz); MS m/z 476.1 (M+H).

Example 184-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-33)

Compound II-33 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.00 (d, 1H, J=2.4 Hz),7.77 (dd, 1H, J=8.4, 2.4 Hz), 7.71 (d, 2H, J=8.8 Hz), 7.34 (d, 2H, J=8.0Hz), 7.15 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=0.8 Hz), 4.93 (s, 2H), 4.43(t, 2H, J=5.2 Hz), 3.76 (t, 2H, J=5.2 Hz), 2.34 (d, 3H, J=0.8 Hz); MSm/z 419.1 (M+H).

Example 194-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-31)

Compound II-31 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.71 (d, 1H, J=0.8 Hz),8.60 (t, 1H, J=2.0 Hz), 8.53 (d, 1H, J=2.4 Hz), 7.99 (d, 1H, J=2.4 Hz),7.77 (dd, 1H, J=8.4, 2.4 Hz), 7.72 (dd, 2H, J=6.6, 2.2 Hz), 7.34 (d, 2H,J=8.0 Hz), 7.15 (d, 1H, J=8.4 Hz), 5.01 (s, 2H), 4.47 (t, 2H, J=5.2 Hz),3.82 (t, 2H, J=5.0 Hz); MS m/z 416.1 (M+H).

Example 204-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-17)

Compound II-17 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.28 (t, 1H, J=7.8 Hz),8.00 (t, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=8.2, 2.6 Hz), 7.68-7.73 (m, 4H),7.35 (dd, 2H, J=8.6, 1.0 Hz), 7.20 (d, 1H, J=8.8 Hz), 5.09 (s, 2H), 4.50(t, 2H, J=5.0 Hz), 3.86 (t, 2H, J=5.0 Hz), 2.77 (s, 3H); MS m/z 429.1(M+H).

Example 217-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-15)

Compound II-15 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 7.98-8.04 (m, 2H),7.68-7.77 (m, 5H), 733 (d, 2H, J=8.0 Hz), 7.14 (d, 1H, J=8.4 Hz), 5.01(s, 2H), 4.48 (t, 2H, J=5.2 Hz), 3.80 (t, 2H, J=5.2 Hz); MS m/z 483.1(M+H).

Example 226-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)picolinonitrile(Compound II-14)

Compound II-14 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 7.96-8.00 (m, 2H),7.69-7.79 (m, 5H), 733 (d, 2H, J=8.0 Hz), 7.15 (d, 1H, J=8.4 Hz), 4.98(s, 2H), 4.46 (t, 2H, J=5.2 Hz), 3.79 (t, 2H, J=5.0 Hz); MS m/z 440.1(M+H).

Example 234-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-10)

Compound II-10 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 7.92 (d, 1H, J=2.8 Hz),7.69-7.75 (m, 3H), 7.34 (d, 2H, J=8.0 Hz), 7.13 (d, 1H, J=8.4 Hz), 4.48(t, 2H, J=5.2 Hz), 3.70 (t, 2H, J=5.2 Hz), 3.53 (d, 2H, J=6.8 Hz),1.13-1.18 (m, 1H), 0.57-0.61 (m, 2H), 0.35-0.40 (m, 2H); MS m/z 378.1(M+H).

Example 244-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-7)

Compound II-7 was prepared according to Examples 1 and 2 using theappropriate starting materials. ¹H-NMR (CD₃OD) δ 8.35 (d, 1H, J=8.8 Hz),8.02-8.05 (m, 2H), 7.93 (d, 1H, J=7.6 Hz), 7.72-7.79 (m, 4H), 7.60 (d,2H, J=8.4 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.16 (d, 1H, J=8.8 Hz), 5.15 (s,2H), 4.43 (t, 2H, J=5.2 Hz), 3.79 (t, 2H, J=5.0 Hz); MS m/z 465.1 (M+H).

Example 257-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-130)

7-Bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (1.0 g, 4.13 mmol)was dissolved in DMF (10 ml) cooled down in a ice/water bath and treatedwith sodium hydride (60% dispersion) (363 mg, 9.08 mmol) portion wise.After 10 min a solution of 2-(chloromethyl)pyrimidine hydrochloride (813mg, 4.96 mmol) in DMF (4 ml) was added, the reaction mixture warmed upto room temperature and quenched with 12 mL of water after it wascomplete. The reaction mixture was extracted with EtOAc and water andthe organic phase was dried, evaporated and purified by silica gelchromatography (95% DCM/MeOH) to afford7-bromo-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

Similar procedure to Example 1 for the synthesis of7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-onewas followed to obtain the title compound using instead of7-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

A mixture of7-bromo-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(50 mg, 0.15 mmol),2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(52 mg, 0.18 mmol), cesium carbonate (146 mg, 0.45 mmol),1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.015mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5mL). The mixture was heated in microwave at 85° C. for 40 min. Themixture was poured into EtOAc and washed with water and brine. Theorganic layer was collected, dried over sodium sulfate and loaded ontosilica gel. A flash column (5% MeOH in EtOAc) and reverse phasechromatography gave7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

MS found for C₂₁H₁₅F₄N₃O₂ as (M+H)⁺ 418.13. ¹H NMR (400 MHz, DMSO-d₆):δ: 8.78 (d, J=4.0 Hz, 2H), 8.09 (d, J=2.0 Hz, 1H), 7.91 (dd, J=2.4, 8.0Hz, 1H), 7.85-7.80 (m, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.41 (t, J=4.8 Hz,1H), 7.17 (d, J=8.4 Hz, 1H), 4.98 (s, 2H), 4.55 (t, J=4.8 Hz, 2H), 3.79(t, J=4.8 Hz, 2H).

Example 267-(4-(difluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-124)

Compound II-124 was prepared according to Example 25 using4-(difluoromethyl)phenylboronic acid. MS found for C₂₁H₁₇F₂N₃O₂ as(M+H)⁺ 382.15. ¹H NMR (400 MHz, DMSO-d₆): δ: 8.77 (d, J=4.8 Hz, 2H),8.00 (d, J=2.4 Hz0, 1H), 7.84-7.77 (m, 4H), 7.63 (d, J=7.6 Hz, 2H), 7.40(t, J=5.2 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.06 (t, J=56.4 Hz, 1H), 4.98(s, 2H), 4.52 (t, J=4.4 Hz, 2H), 3.77 (t, J=5.2 Hz, 2H).

Example 277-(4-cyclopentylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-120)

Compound II-120 was prepared according to Example 25 using4-cyclopentylphenylboronic acid. MS found for C₂₅H₂₅N₃O₂ as (M+H)⁺400.2. ¹H NMR (400 MHz, DMSO-d₆): δ: 8.77 (d, J=4.8 Hz, 2H), 7.90 (d,J=2.4 Hz, 1H), 7.74 (dd, J=2.4, 8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H),7.40 (t, J=4.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.8 Hz, 1H),4.97 (s, 2H), 4.48 (t, J=4.4 Hz, 2H), 3.74 (t, J=5.2 Hz, 2H), 3.00-2.96(m, 1H), 2.01-1.97 (m, 2H), 1.78-1.51 (m, 6H).

Example 287-(4-chloro-3-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-131)

Compound II-131 was prepared according to Example 25 using4-chloro-3-fluorophenylboronic acid. MS found for C20H15ClFN3O2 as(M+H)⁺ 384.09. ¹H NMR (400 MHz, DMSO-d₆): δ: 8.78 (d, J=5.2 Hz, 2H),7.99 (d, J=2.4 Hz0, 1H), 7.83 (dd, J=2.0-8.0 Hz, 1H), 7.72 (d, J=8.8 Hz,1H), 7.62 (t, J=8.0 Hz, 1H), 7.51 (dd, J=1.2-8.4 Hz, 1H), 7.42 (t, J=4.8Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.98 (s, 2H), 4.52 (t, J=4.8 Hz, 2H),3.77 (t, J=4.8 Hz, 2H).

Example 297-(2-tert-butoxypyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-2)

To a mixture of 4-promo-2-tert-butoxypyridine (1.0 g, 4.34 mmol),bis(pinacolato)diboron (1.32 g, 5.22 mmol), potassium acetate (1.28 g,13.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladiummethylene choloride complex (310 mg, 0.43 mmol) was suspended withdegassed dioxane (15 mL) and heated at 85° C. for 60 min. The reactionmixture was diluted with EtOAc, washed with water and brine, dried(MgS(O)₄), filtered and concentrated. The concentrate was purified byflash chromatography on silica gel eluding with 33% percent ethylacetate/hexanes to afford the compound2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

Similar procedure as in Example 25 was followed to obtain the titlecompound using2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinethat was previously prepared.

MS found for C₂₃H₂₄N₄O₃ as (M+H)⁺ 405.13. ¹H NMR (400 MHz, DMSO-d₆): δ:8.77 (d, J=4.8 Hz, 2H), 8.14 (d, J=5.6 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H),7.88 (dd, J=2.4-8.4 Hz, 1H), 7.40 (t, J=4.8 Hz, 1H), 7.18 (d, J=5.6 Hz,1H), 7.12 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 4.97 (s, 2H), 4.53 (t, J=4.8Hz, 2H), 3.77 (t, J=4.4 Hz, 2H), 1.54 (s, 9H).

Example 307-(5-methylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-20)

A mixture of4-(pyrimidin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(50 mg, 0.13 mmol), 2-bromo-5-methylthiophene (28 mg, 0.156 mmol),cesium carbonate (128 mg, 0.39 mmol),1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (9 mg, 0.013mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5ml). The mixture was heated in microwave at 85° C. for 40 min. Themixture was poured into EtOAc and washed with water and brine. Theorganic layer was collected, dried over sodium sulfate and loaded ontosilica gel. A flash column (5% MeOH in EtOAc) and reverse phasechromatography gave7-(5-methylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

MS found for C19H17N3O2S as (M+H)⁺ 352.09. ¹H NMR (400 MHz, DMSO-d₆):¹H-NMR (DMSO) δ: 8.70 (d, J=4.0 Hz, 2H), 7.80 (d, J=2.0 Hz, 1H), 7.68(dd, J=2.0-8.4 Hz, 1H), 7.40 (t, J=4.8 Hz, 1H), 7.23 (d, J=3.2 Hz, 1H),7.05 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H), 4.95 (s, 2H), 4.46 (t,J=4.8 Hz, 2H), 3.73 (t, J=4.8 Hz, 2H), 2.48 (s, 3H).

Example 311-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl)cyclopentanecarbonitrile(Compound II-122)

To a solution of 2-(4-bromophenyl)acetonitrile (1.0 g, 5.10 mmol) and1,4-dibromobutane (0.67 ml, 5.6 mmol) in THF (10 ml) was added potassiumbis(trimethylsilyl) amide (2.23 g, 11.2 mmol) and tetra-n-butylammoniumbromide (164 mg, 0.51 mmol). The mixture was stirred for 2 h and thenquenched with 1N HCl. Ethyl acetate was added, the layers separated andthe organic layer was washed with water and brine. Drying, solventevaporation and flash chromatography (silica gel, 20% EtOAc/hexanes)gave 1-(4-bromophenyl)cyclopentanecarbonitrile.

Similar procedure as in Example 30 was followed to obtain the titlecompound using 1-(4-bromophenyl)cyclopentanecarbonitrile.

MS found for C26H24N4O2 as (M+H)⁺ 425.21. ¹H NMR (400 MHz, DMSO-d₆):¹H-NMR (DMSO) δ: 8.72 (d, J=4.0 Hz, 2H), 7.90 (d, J=2.4 Hz, 1H), 7.74(dd, J=2.4-8.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H),7.35 (t, J=4.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 4.92 (s, 2H), 4.45 (t,J=4.4 Hz, 2H), 3.71 (t, J=4.8 Hz, 2H), 2.37-2.34 (m, 2H), 2.05-2.02 (m,2H), 1.85-1.83 (m, 4H).

Example 327-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-123)

Compound II-123 was prepared according to Example 30 using1-bromo-4-ethoxybenzene. MS found for C22H21N3O3 as (M+H)⁺ 376.15. ¹HNMR (400 MHz, DMSO-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.86 (d, J=2.4 Hz0,1H), 7.71 (dd, J=2.8-8.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.40 (t, J=4.8Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.96 (s, 2H),4.47 (t, J=4.8 Hz, 2H), 4.06-4.01 (m, 2H), 3.74 (t, J=4.4 Hz, 2H),1.34-1.30 (m, 3H).

Example 337-(4-(difluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-119)

Compound II-119 was prepared according to Example 30 using1-bromo-4-(difluoromethoxy)benzene. MS found for C21H17F2N3O3 as (M+H)⁺398.13. ¹H NMR (400 MHz, DMSO-d₆): ¹H-NMR (DMSO) δ: 8.77 (d, J=4.8 Hz,2H), 7.92 (d, J=2.0 Hz0, 1H), 7.77 (dd, J=2.4-8.4 Hz, 1H), 7.68 (d,J=8.4 Hz, 2H), 7.40 (t, J=4.8 Hz, 1H), 7.26 (t, J=74.0 Hz, 2H), 7.23 (d,J=8.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.97 (s, 2H), 4.50 (t, J=4.8 Hz,2H), 3.75 (t, J=4.8 Hz, 2H).

Example 344-(4-fluorobenzyl)-7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-22)

Compound VI-22 was prepared according to Example 30 using1-(chloromethyl)-4-fluorobenzene and 4-bromo-1-methylpyridin-2(1H)-one.MS found for C22H19FN2O3 as (M+H)⁺ 379.27 ¹H NMR (400 MHz, DMSO-d₆): δ:8.01 (d, J=2.4 Hz, 1H), 7.83 (dd, J=2.0-8.4 Hz, 1H), 7.75 (d, J=6.8 Hz,1H), 7.42-7.38 (m, 2H), 7.17 (t, J=9.2 Hz, 2H), 7.10 (d, J=8.0 Hz, 1H),6.63 (s, 1H), 6.56 (dd, J=2.0-7.2 Hz, 1H), 4.74 (s, 2H), 4.27 (t, J=4.8Hz, 2H), 3.56 (t, J=4.8 Hz, 2H), 3.42 (s, 3H).

Example 357-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-23)

Compound VI-23 was prepared according to Example 30 using5-bromo-1-isopropyl-2-methyl-1H-imidazole. MS found for C21H23N5O2 as(M+H)⁺ 378.14 ¹H NMR (400 MHz, DMSO-d₆): δ: 8.77 (d, J=4.8 Hz, 2H), 8.15(s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.40 (t, J=4.8 Hz, 2H), 7.10 (d, J=8.0Hz, 1H), 6.68 (s, 1H), 4.95 (s, 2H), 4.52 (t, J=4.8 Hz, 1H), 4.32-4.29(s, 1H), 3.77 (t, J=4.8 Hz, 2H), 2.41 (s, 3H), 1.34 (d, J=6.8 Hz, 6H).

Example 367-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-13)

A mixture of7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(200 mg, 0.69 mmol), 4-bromo-1-methylpyridin-2(1H)-one (156 mg, 0.83mmol), cesium carbonate (674 mg, 2.07 mmol),1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (49 mg, 0.069mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5mL). The mixture was heated in microwave at 85° C. for 40 min. Themixture was poured into EtOAc and washed with water and brine. Theorganic layer was collected, dried over sodium sulfate and loaded ontosilica gel. A flash column (5% MeOH in EtOAc) and reverse phasechromatography gave7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(50 mg, 0.185 mmol) was dissolved in DMF (3 mL) and cooled down in aice/water bath and treated with sodium hydride (60% dispersion) (17 mg,0.41 mmol) portion wise. After 10 min a solution of2-(chloromethyl)pyrimidine hydrochloride (37 mg, 0.22 mmol) in DMF (2mL) was added and the reaction mixture was warmed up to room temperatureand quenched with 6 mL of water after it was complete. The reactionmixture was extracted with EtOAc and water and the organic phase wasdried, evaporated and purified by silica gel chromatography (95%DCM/MeOH) and then purified by reverse phase chromatography to afford7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

MS found for C20H18N4O3 as (M+H)⁺ 363.19. ¹H NMR (400 MHz, DMSO-d₆) δ:8.77 (d, J=5.2 Hz, 2H), 7.99 (d, J=2.8 Hz0, 1H), 7.83 (dd, J=2.4-8.4 Hz,1H), 7.73 (d, J=7.2 Hz, 1H), 7.40 (t, J=5.2 Hz, 1H), 7.12 (d, J=8.8 Hz,1H), 6.60 (d, J=1.6 Hz, 1H), 6.53 (dd, J=2.0-7.2 Hz, 1H), 4.97 (s, 2H),4.54 (t, J=4.8 Hz, 2H), 3.77 (t, J=4.4 Hz, 2H), 3.42 (s, 3H).

Example 377-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-12)

Compound VI-12 was prepared according to Example 36 using2-(chloromethyl)pyridine hydrochloride. MS found for C21H19N3O3 as(M+H)⁺ 362.18. ¹H NMR (400 MHz, DMSO-d₆): δ: 8.73 (s, 1H), 8.25 (s, 1H),7.99 (s, 1H), 7.84-7.75 (m, 4H), 7.12 (d, J=8.0 Hz, 1H), 6.60-6.53 (m,2H), 5.02 (s, 2H), 4.44 (s, 2H), 3.79 (s, 2H), 3.41 (s, 3H).

Example 387-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-4)

Compound VI-4 was prepared according to Example 36 using7-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one,2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineand 2-(chloromethyl)pyridine hydrochloride.

MS found for C24H25N3O3 as (M+H)⁺ 404.18. ¹H NMR (400 MHz, DMSO-d₆): δ:8.52 (d, J=4.8 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H),7.87 (dd, J=2.0-8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.35 (d, J=8.0 Hz, 1H),7.29 (dd, J=4.8-6.8 Hz, 1H), 7.21 (d, J=5.6 Hz, 1H), 7.12 (d, J=8.4 Hz,1H), 6.91 (s, 1H), 4.85 (s, 2H), 4.39 (t, J=4.4 Hz, 2H), 3.69 (t, J=4.8Hz, 2H), 1.54 (s, 9H).

Example 397-(2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-3)

Compound VI-3 was generated after the acidic hydrolysis of Compound VI-4with formic acid. MS found for C20H17N3O3 as (M+H)⁺ 348.13 ¹H NMR (400MHz, DMSO-d₆): δ: 11.56 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 7.98 (d, J=2.4Hz, 1H), 7.82-7.75 (m, 2H), 7.42 (d, J=6.8 Hz, 1H), 7.35 (d, J=7.6 Hz,1H), 7.28 (dd, J=4.8-6.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.53 (s, 1H),6.47 (dd, J=1.6-6.4 Hz, 1H), 4.85 (s, 2H), 4.39 (t, J=4.4 Hz, 2H), 3.69(t, J=4.4 Hz, 2H).

Example 404-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-73)

To a solution of Compound 1-A (20 g, 0.083 mol, 1 eq.) and Compound 40-A(25 g, 0.15 mol, 1.8 eq.) in DMF (150 mL), NaOH solution (20 mL, 10M, 5eq.) was slowly added at room temperature (slightly exothermic) andstirred at r.t. for 10 min, followed by heating at 95° C. for 2 h. Aftercooling the reaction mixture, ethyl acetate (200 mL) was added and theorganic layer was separated. The organics was washed with water (20 mL),brine, dried over sodium sulphate and concentrated.

The residue was dissolved in 1,4-dioxane (50 mL) and to this 4N HCl indioxane (50 mL) and conc. HCl (2 mL) was added and stirred at roomtemperature for 4 h, filtered the precipitate, washed with ethyl acetateand dried. Compound 40-B obtained (30 g) was a light yellow solid.

To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol,1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottomflask, solvent (150 mL, toluene/isopropano/water: 2/1/1) was added andstirred under nitrogen for 10 min. To the above solution the palladiumcatalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85° C. for 2h. The reaction mixture was diluted with ethyl acetate, separated theorganic layer and filtered the organic layer through a plug of celiteand silica gel and concentrated. Column purification on silica gel usingethyl acetate/hexane as eluent provided Compound II-73 (13 g).

To a solution of Compound II-73 (26 g) in 1,4-dioxane (25 mL), 4NHCl/dioxane (25 mL) was added followed by conc. HCl (2 mL) and stirredat room temperature for 4 h. Solvent was distilled off, dichloromethanewas added and distilled off and to the residue, ethyl acetate (150 mL)was added and stirred at room temperature overnight and filtered theprecipitate, washed with ethyl acetate, hexane and dried under vacuum.Compound II-73-HCl obtained (24.8 g) was a white solid.

¹H-NMR (CDCl₃) δ 8.72 (d, 2H, J=5.2 Hz), 8.17 (d, 1H, J=2.4 Hz),7.59-7.63 (m, 3H), 7.26 (d, 2H, J=3.2 Hz), 7.22 (t, 1H, J=4.8 Hz), 7.10(d, 1H, J=8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J=5.0 Hz), 3.77 (t, 2H,J=5.0 Hz); MS m/z 416.1 (M+H).

Example 417-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-128)

7-Bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (2.0 g),4-trifluoromethoxyphenylboronic acid (2.2 g) and potassium carbonate(2.0 g) were combined in a mixture of toluene (20 mL), isopropanol (10mL) and water (10 mL) and the resulting suspension was degassed withnitrogen. Palladium chloride dppf complex was added (0.42 g) and thereaction was heated overnight at 85° C. After cooling aqueous layer wasdiscarded and the organic layer was diluted 2-fold with ethyl acetate,dried over MgS(O)₄ and concentrated. Recrystallization was conducted bydissolving in a minimum necessary amount of dichloromethane and crushingwith excess hexane, resulting in7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-oneas a grey solid (1.43 g).

¹H NMR: 8.42 (t, 1H); 8.12 (d, 1H); 7.86-7.76 (m, 5H); 7.13 (d, 1H);4.38 (t, 2H); 3.37 (quartet, 2H).

Example 424-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-129)

7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(50 mg) was dissolved in dry THF and the NaH suspension (6 mg, 60% inoil) was added, followed shortly by2-(chloromethyl)imidazo[1,2-a]pyridine (29 mg) and stirred overnight atroom temperature. Worked up with ethyl acetate and pH 7 buffer organiclayer dried over MgS(O)₄ and concentrated. Purification was conducted onnormal phase (CH₂Cl₂/10% EtOH in ethyl acetate gradient) followed byreverse-phase (ACN/H₂O, 0.1% TFA). Resulting glassy solid was dissolvedin dioxane, diluted 10-fold with 0.1N HCl and lyophilized resulting in4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-onehydrochloride salt as a white solid (42.2 mg).

¹H NMR: 7.95 (s, 1H); 7.53 (d, 2H); 7.36 (m, 2H); 7.31 (d, 2H); 7.20 (d,1H); 5.30 (s, 2H); 2.16 (s, 3H); ¹⁹F NMR: −58.36 (s); MS (ESI+): 391.0(base peak, M+H⁺); 803.2 (2M+Na⁺).

Example 438-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-1)

To a cooled (0° C.) solution of Compound 43-A (1.368 g, 5.0 mmol) inanhydrous THF (10 mL) was added dropwise 2-aminoethanol (1.833 g, 30.0mmol) in THF (10 mL) with stir. After completion of addition, thereaction mixture was allowed to warm to room temperature overnight. Themixture was concentrated in vaccuo, taken up in EA-H₂O (100-50 mL),transferred to separation funnel, the aqueous layer was extracted withEA (50 mL×3), combined organic phase was washed with 0.1 N HCl (100mL×2), dried, concentrated to give Compound 43-B (1.355 g). LCMS m/z226.0 (M+H), 228.0 (M+H+2), anal HPLC>98%. It was used directly in thenext step without further purification.

To a solution of Compound 43-B (920 mg, 3.11 mmol) and4-trifluoromethylphenylboronic acid Compound 43-C (886 mg, 4.66 mmol) inDMF (6 mL) was added K₂CO₃ (1.932 g, 13.98 mmol), triethylamine (1 mL)and H₂O (1 mL). The reaction mixture was stirred for 5 min under anatmosphere of dry N₂. PdCl₂(dppf) (68 mg, 0.09 mmol) was added and theresulting mixture was heated at 130° C. for 30 min in a Biotagemicrowave. The reaction mixture was cooled, diluted with EtOAc (30 mL),filtered through a layer of celite, washed with 20% DMF in EtOAc (60mL), combined filtrate concentrated in vaccuo. To the resulting slurrywas added 1% MOH in CH₂Cl₂ (10 mL), filtered and the filtrate wassubjected to Yamazen chromatography, eluting with a gradient of EtOAc inCH₂Cl₂ to afford the desired product Compound 43-D (823 mg, 2.26 mmol,73%). LCMS m/z 364.1 (M+H), anal HPLC>92% in purity.

To a cooled (0° C.) solution of Compound 43-D (73 mg, 0.20 mmol) inanhydrous DMF (3 mL) was added 95% NaH (10 mg, 0.40 mmol) in 3 portionsand the resulting mixture was allowed to warm to room temperature underan atmosphere of N₂ for 3 h. The reaction was quenched with solid NH₄Cl(159 mg, 3.0 mmol), then EtOAc-H₂O (30 mL and 10 mL) was added,transferred to a separation funnel. The aqueous layer was extracted withEtOAc (3×10 mL), combined organic phase dried (MgS(O)₄), concentrated.The crude mixture was subjected to Yamazen chromatography, eluting witha gradient of EtOAc in CH₂Cl₂ (0% to 25%) to afford Compound IX-1 (34mg, 0.10 mmol, 50%).

LCMS m/z 344.0 (M+H), anal HPLC>96% in purity. ¹H NMR (400 MHz; DMSO-d6)δ 7.97 (d, J=2.3 Hz, 1H); 7.93 (dd, J=8.3, 2.4 Hz, 1H); 7.90 (s, 1H);7.85 (m, 4H); 7.35 (d, J=8.2 Hz, 1H); 4.14 (m, 2H); 3.47 (m, 2H). ¹⁹FNMR (400 MHz; DMSO-d6) δ −61.50 (s, 3F).

Example 442-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-3)

A mixture of chloromethyl-5-chloropyrimidine (82 mg, 0.50 mmol),Compound IX-1 (17 mg, 0.05 mmol), K₂CO₃ (169 mg, 1.22 mmol),triethylamine (0.5 mL) anhydrous DMF (3 mL) in a Biotage microwave vialwas capped and irradiated at 130° C. for 30 min in a Biotage microwave.The reaction was cooled, taken up in EtOAc (30 mL), filtered through asilica gel plug and concentrated. The crude mixture was subjected toGilson preparative HPLC, eluting with a gradient of ACN in H₂O (5% to95%) to afford Compound IX-3 (19 mg, 0.04 mmol, 80%).

LCMS m/z 470.0 (M+H), 472.0 (M+H+2), anal HPLC>98% in purity, ¹H NMR(400 MHz; acetone-d6) 8.77 (s, 2H); 8.04 (d, J=2.3 Hz, 1H); 7.95 (m,3H); 7.84 (d, J=8.4 Hz, 2H); 7.37 (d, J=8.4 Hz, 1H); 4.57 (s, 2H); 4.41(m, 2H); 4.00 (m, 2H). ¹⁹F NMR (400 MHz; acetone-d6) −63.62 (s, 3F).

Example 458-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-5)

Compound IX-5 was prepared according to Example 44 using the appropriatestarting materials [m/z 360.1, M+H].

Example 462-(2,2,2-trifluoroeth-1-yl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-4)

Compound IX-4 was prepared according to Example 44 using the appropriatestarting materials [m/z 426.1, M+H].

Example 472-(2,2,2-trifluoroeth-1-yl)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-7)

Compound IX-7 was prepared according to Example 44 using the appropriatestarting materials.

Example 482-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-2)

Compound IX-2 was prepared according to Example 44 using the appropriatestarting materials [m/z 436.1, M+H].

Example 492-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-6)

Compound IX-6 was prepared according to Example 44 using the appropriatestarting materials.

Example 502-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-8)

Compound IX-8 was prepared according to Example 44 using the appropriatestarting materials.

Example 512-(cyclopropylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-9)

Compound IX-9 was prepared according to Example 44 using the appropriatestarting materials.

Example 522-(2-methoxyeth-1-yl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-sulfone(Compound IX-10)

Compound IX-10 was prepared according to Example 44 using theappropriate starting materials [m/z 402.1, M+H].

Example 534-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-4)

Compound II-4 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.01 (d, 1H,J=2.0 Hz), 7.78 (dd, 1H, J=8.8, 2.4 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.35(d, 2H, J=8.0 Hz), 7.16 (d, 1H, J=8.8 Hz), 5.07 (s, 2H), 4.49 (t, 2H,J=5.0 Hz), 3.75-3.83 (m, 3H), 2.41-2.47 (m, 4H), 2.00-2.21 (m, 2H); MSm/z 460.1 (M+H).

Example 544-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-75)

Compound II-75 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.35 (d, 1H,J=4.8 Hz), 8.00 (d, 1H, J=2.4 Hz), 7.70-7.77 (m, 3H), 7.66 (d, 1H, J=7.6Hz), 7.35 (d, 1H, J=8.0 Hz), 7.26-7.29 (m, 2H), 7.13 (d, 1H, J=8.0 Hz),5.01 (s, 2H), 4.25 (t, 2H, J=5.2 Hz), 3.68 (t, 2H, J=5.2 Hz), 2.43 (s,3H); MS m/z 429.1 (M+H).

Example 557-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-105)

Compound II-105 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d, 2H,J=4.8 Hz), 8.02 (s, 1H), 7.71-7.75 (m, 2H), 7.54-7.59 (m, 2H), 7.38 (t,1H, J=4.8 Hz), 7.18 (d, 1H, J=8.4 Hz), 5.07 (s, 2H), 4.62 (t, 2H, J=4.8Hz), 3.86 (t, 2H, J=4.8 Hz); MS m/z 418.1 (M+H).

Example 567-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-110)

Compound II-110 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d, 2H,J=4.8 Hz), 7.88 (d, 1H, J=2.4 Hz), 7.82 (s, 1H), 7.69 (d, 1H, J=7.6 Hz),7.60-7.63 (m, 2H), 7.38 (t, 1H, J=5.0 Hz), 7.17 (d, 1H, J=8.0 Hz), 5.07(s, 2H), 4.62 (t, 2H, J=4.8 Hz), 3.86 (t, 2H, J=4.8 Hz); MS m/z 434.0(M+H).

Example 577-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-113)

Compound II-113 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 9.08 (d, 1H,J=5.2 Hz), 8.01 (d, 1H, J=2.0 Hz), 7.76-7.79 (m, 2H), 7.71 (d, 2H, J=9.2Hz), 7.34 (d, 2H, J=8.0 Hz), 7.17 (d, 1H, J=8.4 Hz), 5.16 (s, 2H), 4.63(t, 2H, J=5.0 Hz), 3.88 (t, 2H, J=4.8 Hz); MS m/z 484.1 (M+H).

Example 587-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-126)

Compound II-126 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.74 (d, 1H,J=5.2 Hz), 8.13 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=6.4 Hz), 7.77 (dd, 1H,J=8.2, 2.2 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.48 (dd, 1H, J=7.4, 5.0 Hz),7.34 (d, 2H, J=8.4 Hz), 7.16 (d, 1H, J=8.8 Hz), 5.18 (s, 2H), 4.57 (t,2H, J=4.8 Hz), 3.81 (t, 2H, J=5.2 Hz); MS m/z 483.1 (M+H).

Example 594-(oxazol-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(211)-one(Compound II-127)

Compound II-127 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.00 (d, 1H,J=2.4 Hz), 7.92 (s, 1H), 7.77 (dd, 1H, J=8.6, 2.2 Hz), 7.72 (d, 2H,J=8.4 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.14-7.17 (m, 2H), 4.99 (s, 2H), 4.44(t, 2H, J=5.0 Hz), 3.78 (t, 2H, J=5.0 Hz); MS m/z 405.0 (M+H).

Example 604-(2-(benzyloxy)ethyl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-7)

6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione (5.0 g, 20.66 mmol),iodomethane (1.94 mL, d=2.28, 4.4 g, 31.0 mmol, 1.5 equiv.) and Na₂CO₃(4.38 g, 41.3 mmol, 2 equiv.) were placed in a round bottomed flask. Tothe flask were added DMF (40 mL) at ambient temperature. The mixture wasstirred overnight at room temperature and then filtered through a glassfilter. Obtained filtrate was diluted with water to form precipitates.The precipitates were dissolved in EtOAc and the solution was dried overMgS(O)4. The solvent was removed under reduced pressure. At this point,since the conversion was ˜50%, K₂CO₃ (14.3 g, 103.3 mmol, 5 equiv.) andiodomethane (2.58 mL, d=2.28, 41.3 mmol, 2.0 equiv.) were added to thesolution of the crude material in DMF. The mixture was heated at 30° C.so that the reaction can go to completion and then filtered through aglass filter. Obtained filtrate was diluted with water to formprecipitates. Formed precipitates were filtered through a glass filterto give the desired product(6-bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione). This was used forthe subsequent step without further purification.

6-Bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (5.29 g, 20.66 mmol)and glycine (1.7 g, 22.73 mmol, 1.1 equiv.) were dissolved in AcOH (100mL) in a round bottomed flask. The mixture was heated under refluxconditions for 2 hours. The mixture was purified by automated silica-gelcolumn chromatography using EtOAc/hexane gradient as the eluent. Thepurification give the desired product(7-bromo-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione,colorless powder, 446.7 mg).

7-Bromo-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (446.7mg, 1.661 mmol), 4-trifluoromethoxyboronic acid (445.0 mg, 2.159 mmol,1.3 equiv.) Pd(dppf)Cl₂.CH₂Cl₂ (120.0 mg, 0.166 mmol, 10 mol %) andK₂CO₃ (482.0 mg, 3.49 mmol, 2.1 equiv.) were dissolved in a mixedsolvents, H₂O/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL roundbottomed flask under a nitrogen atmosphere. The mixture was heated at60° C. for 64 h. The mixture was purified by automated silica-gel columnchromatography using EtOAc/hexane gradient as the eluent. Thepurification give the desired product(1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione,415.0 mg).

1-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(50.0 mg, 0.143 mmol) and NaH (17 mg, 0.428 mmol, 3.0 equiv.) wereplaced in a 2-5 mL Smith process vial under a nitrogen atmosphere. Tothe vial was added DMF (5 mL) to observe hydrogen extlusion. And then((2-bromoethoxy)methyl)benzene (45 μL, 0.285 mmol, d=0.135, 2 equiv.)was added at room temperature. After stirring for 50 min, the reactionwas quenched with AcOH. Resulting mixture was directly injected to apreparative HPLC to give the desired product(4-(2-(benzyloxy)ethyl)-1-methyl-7-(4-(trifluoromethoxy)-phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione,42.7 mg) as a light yellow film.

LCMS (EI: 70 eV) 503 (M⁺+Na), 486 (M⁺+1).

Example 614-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-9)

Procedure to 61-B To a mixture of compound 61-A (4.380 g, 20.0 mmol),N-Boc diamine (5.000 g, 31.2 mmol) and EDC (5.600 g, 38.74 mmol) inanhydrous CH₂Cl₂ (80 mL) was added dropwise Hunig's base (10 mL, 56.16mmol) with stir. After completion of addition, the reaction mixture wasconcentrated in vaccuo, taken up in EA-H₂O (200-100 mL), transferred toseparation funnel, the aqueous layer was extracted with EA (100 mL×3),combined organic phase was washed with 0.1 N HCl (100 mL×2), dried,concentrated, column chromatographed using Yamazen, eluting withEaOAc/n-hexane to give compound 61-B (6.386 g, 17.67 mmol, 88%). LCMSm/z 362.0 (M+H), anal HPLC>90%. It was used directly in the next stepwithout further purification.

Procedure to Compound 61-C Standard Suzuki coupling as described above,starting from compound 61-B (658 mg, 1.8 mmol), a pale yellow solid 61-D(610 mg, 1.4 mmol, 79%) was obtained using Yamazen chromatographyeluting with EaOAc/n-hexane, LCMS m/z 327.1 (M-t-Butyl), 876.3 (2M+Na),it was used directly in the next step without further purification.

Procedure to Compound 61-D and 61-E To a anhydrous DMF (30 mL) solutionof compound C (213 mg, 0.500 mmol) and chloromethyl pyrimidine HCl salt(248 mg, 1.50 mmol) was added slowly 95% NaH (65 mg, 2.7 mmol) andstirred 5 min. Another portion of 95% NaH (55 mg, 2.3 mmol) was added,stirred for 5 min. The crude mixture was quenched by 30% aqueous NH₄Cl(40 mL), extracted with EtOAc (3×100 mL), combined organic phase waswashed with saturated NaHCO₃ (100 mL), brine (100 mL), dried,concentrated in vaccuo. Reverse-phase HPLC was used to obtain a yellowsolid 61-D (75 mg, 0.14 mmol, 29%). LCMS m/z 519.2 (M+H). It was useddirectly in the next step without further purification.

To a solution of compound 61-D (70 mg, 0.13 mmol) in DCM (5.0 mL) wasadded TFA (2.0 mL) and stirred overnight. Then it was concentrated invaccuo, only one single peak in LCMS as compound 61-E, m/z 419.1 (M+H),anal HPLC>95 in purity.

Procedure to compound X-9 To a anhydrous DMF solution (15 mL) of theabove compound 61-E (54 mg, 0.13 mmol) was added Hunig's base (2 mL),capped in a Biotage microwave vial and subjected to microwave heating at150° C. for 40 min. The reaction mixture was filtered, concentrated invaccuo and subjected to Gilson preparative HPLC, eluting with a gradientof ACN in H₂O (5% to 95%) to afford X-9 (16 mg, 0.04 mmol, 31%). LCMSm/z 399.1 (M+H), anal HPLC>98% in purity.

Example 621-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one(Compound X-10)

Procedure to compound X-10 To a anhydrous DCM solution (3 mL) of thecompound X-9 (14 mg, 0.035 mmol) was added paraformaldehyde (0.5 mL) andH₂O (1 mL), stirred for 5 min, THF (1 mL) was added to help solubility.After 5 min, borohydride (63 mg, 0.31 mmol) was added, stirred for 30min until the starting material disappeared in LCMS. The crude mixturewas quenched by 30% aqueous NH₄Cl (10 mL), extracted with EtOAc (3×30mL), combined organic phase was washed with saturated NaHCO₃ (30 mL),brine (30 mL), dried, concentrated in vaccuo. Reverse-phase HPLC wasused to obtain a yellow solid X-10 (6 mg, 0.015 mmol, 42%). LCMS m/z412.1 (M+H), anal HPLC>98%.

Example 634-((1-methyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-186)

Compound II-186 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. The Suzuki coupling wasperformed under standard conditioned explained in the other proceduresusing Pd(dppf)Cl₂.

Alkylation of the amide was performed using sodium hydride following thestandard procedure to provide the final products.

Mass (M+H)⁺ 418.1. ¹H NMR (400 MHz; dmso-d₆) δ 7.93 (s, 1H); 7.75 (m,3H); 7.58 (m, 2H); 7.42 (m, 2H); 4.86 (m, 2H); 4.18 (m, 2H); 3.75 (s,3H); 3.65 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −57.26 (s, 3F).

Example 644-(2-morpholinoethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-188)

Compound II-188 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 437.1.

Example 654-((5-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-172)

Compound II-172 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 430.1. ¹H NMR (400MHz; DMSO-d6) δ 8.50 (m, 2H); 7.94 (s, 1H); 7.78 (m, 3H); 7.41 (d, J=8.5Hz, 2H); 7.13 (d, J=8.1 Hz, 1H); 4.86 (s, 2H); 4.38 (m, 2H); 3.71 (m,2H); 2.48 (s, 3H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −57.26 (s, 3F).

Example 664-((6-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-175)

Compound II-175 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 430.1 ¹H NMR (400MHz; CD₃OD) δ 8.48 (s, 1H); 8.41 (s, 1H); 7.97 (s, 1H); 7.73 (m, 3H);7.32 (d, J=8.6 Hz, 2H); 7.13 (d, J=8.6 Hz, 1H); 4.95 (s, 2H); 4.46 (m,2H); 3.80 (m, 2H); 3.30 (s, 3H). ¹⁹F NMR (400 MHz; CD₃OD) δ −56.96 (s,3F).

Example 674-((1-benzyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-187)

Compound II-187 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 494.1. ¹H NMR (400MHz; dmso-d₆) δ 7.00-8.00 (m, 12H); 5.32 (s, 2H); 4.82 (s, 2H); 4.26 (m,2H); 3.49 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −57.25 (s, 3F).

Example 684-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-189)

Compound II-189 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 454.1. ¹H NMR (400MHz; dmso-d₆) δ 6.80-8.50 (m, 12H); 5.36 (s, 2H); 4.82 (m, 2H); 4.24 (m,2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −57.38 (s, 3F).

Example 69 tert-butyl2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate(Compound III-40)

Decarboxylation of the amide was performed using 1M BH₃ in THF for 1-5days following the standard procedure to provide amine 69-A. This wasfollowed by a standard HATU catalyzed condensation reaction to affordCompound III-40. Mass (M+H)⁺ 543.2.

Example 70(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-42)

Compound III-40 was deprotected using TFA in dichloromethane in astandard procedure to give Compound III-42. Mass (M+H)⁺ 443.1.

Example 711-(2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone(Compound III-48)

Standard acylation using acetic anhydride at room temperature ofCompound III-42 afforded Compound III-48. Mass (M+H)⁺ 485.1.

Example 72(1-methyl-1H-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-32)

Compound III-32 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 402.1.

Example 73(1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-33)

Compound III-33 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 388.1.

Example 74(1-((1H-imidazol-1-yl)methyl)cyclopropyl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-34)

Compound III-34 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 442.1.

Example 75(1-methyl-1H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-37)

Compound III-37 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 402.1.

Example 76 (R)-tert-butyl2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)pyrrolidine-1-carboxylate(Compound III-52)

Compound III-52 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 491.2.

Example 77(1H-1,2,3-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-49)

Compound III-49 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 389.1.

Example 78(1H-1,2,4-triazol-3-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-50)

Compound III-50 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 389.1.

Example 79(3-amino-1H-1,2,4-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-51)

Compound III-51 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 404.1.

Example 80(R)-pyrrolidin-2-yl(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-53)

Compound III-53 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 391.1.

Example 81(1-phenyl-1H-1,2,3-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-54)

Compound III-54 was prepared according to the Examples disclosed hereinusing the appropriate starting materials.

Example 82(R)-1-(2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)pyrrolidin-1-yl)ethanone(Compound III-55)

Compound III-55 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 433.1.

Example 83(1H-imidazol-2-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-56)

Compound III-56 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 404.1.

Example 84(S)-4-benzyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-132)

A solution of 5-bromo-2-fluorobenzoic acid (1 mmol), benzyl (S)-valinol(1 mmol), HATU (1 mmol) and diisopropylethylamine (3 mmol) in DMF (3 mL)was stirred at room temperature for 30 minutes. The reaction mixture waspoured into a 1:1 solution of 1M HCl and brine and extracted with ethylacetate. The organic layer was washed with saturated sodium bicarbonatesolution and brine, dried and concentrated. The resided was taken up ina mixture of toluene, isopropanol and water (1 mL each) and added to aflask containing 4-trifluoromethylphenyl boronic acid (3 mmol), K₂CO₃ (3mmol) and dppfPdCl₂ (40 mg) under nitrogen. The reaction mixture wasstirred at 90° C. for 1 h. The organic layer was separated andconcentrated before being purified by flash chromatography (rf=0.28 in2:1 hexanes/ethyl acetate) to give a viscous oil. The product wasdissolved in DMF (5 mL) and sodium hydride was added (5 mmol). Thereaction mixture was stirred at room temperature for 40 minutes and waspoured into a 1:1 solution of 1M HCl and brine and extracted with ethylacetate. The organic layer was washed with saturated sodium bicarbonatesolution and brine, dried and concentrated before being purified byflash chromatography (rf=0.59 in 2:1 hexanes/ethyl acetate) to give(S)-4-benzyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-oneas an oil.

To a solution of the above product in chloroform was added NBS (2.5equiv) and N-methylacetamide (10 mol %). The reaction was stirred for 18hours at room temperature before being concentrated under vacuum. Theresidue was dissolved in ethyl acetate (10 mL) and 1M NaOH solution wasadded (10 mL). The mixture was stirred vigorously for 5 minutes and theorganic layer was separated, washed with brine and concentrated. Flashchromatography (rf=0.10 in 2:1 hexanes/ethyl acetate) gave thedebenzylated product.

To a solution of the above product (20 mg) and 2-chloromethylpyrimidineHCl salt (30 mg) in DMF was added sodium hydride (40 mg) and thereaction was stirred for 1 h at room temperature. The reaction mixturewas quenched with 1M HCl and purified by preparative HPLC to give(S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-oneTFA salt as a white powder.

Example 85(2S,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-51)

Compound II-51 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₇F₃N₂O₂×TFA. 363.1 (M+1).¹H NMR (DMSO) δ 8.34 (d, J=2.8 Hz, 1H), 8.20 (br, 3H), 7.85 (m, 5H),7.16 (d, J=8.4 Hz, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.16 (m, 2H), 3.96 (m,1H), 3.83 (br, 1H), 3.58 (m, 1H), 2.54 (m, 1H), 1.80 (m, 1H). ¹⁹F NMR(DMSO) δ −61.4 (s, 3F).

Example 86(R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-8)

Compound II-8 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₄H₂₁F₃N₄O₂×2-TFA. 455.1(M+1).

Example 87(S)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-9)

Compound II-9 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₄H₂₁F₃N₄O₂×2-TFA. 455.1(M+1).

Example 88(S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-12)

Compound II-12 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₂×TFA. 414.1 (M+1).¹H NMR (DMSO) δ 8.77 (d, J=5.2 Hz, 2H), 8.38 (d, J=2.4 Hz, 1H), 7.85 (m,5H), 7.40 (t, J=5.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.10 (J=17.0 Hz,1H), 4.79 (d, J=17.0 Hz, 1H), 4.60 (m, 2H), 4.05 (m, 1H). 1.22 (d, J=6.8Hz, 3H). ¹⁹F NMR (DMSO) δ −61.37 (s, 3F).

Example 89(R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-13)

Compound II-13 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₂×TFA. 414.1 (M+1).¹H NMR (DMSO) δ 8.77 (d, J=5.2 Hz, 2H), 8.38 (d, J=2.4 Hz, 1H), 7.85 (m,5H), 7.40 (t, J=5.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.10 (J=17.0 Hz,1H), 4.79 (d, J=17.0 Hz, 1H), 4.60 (m, 2H), 4.05 (m, 1H). 1.22 (d, J=6.8Hz, 3H). ¹⁹F NMR (DMSO) δ −61.37 (s, 3F).

Example 90(S)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-18)

Compound II-18 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₇H₁₄F₃NO₂. 322.1 (M+1). ¹HNMR (DMSO) δ 8.41 (d, J=4.4 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.85 (m,5H), 7.16 (d, J=8.4 Hz, 1H), 4.22 (m, 2H), 3.68 (br, 1H), 1.15 (d, J=6.4Hz, 3H).

Example 91(R)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-19)

Compound II-19 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₇H₁₄F₃NO₂. 322.1 (M+1). ¹HNMR (DMSO) δ 8.41 (d, J=4.4 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.85 (m,5H), 7.16 (d, J=8.4 Hz, 1H), 4.22 (m, 2H), 3.68 (br, 1H), 1.15 (d, J=6.4Hz, 3H).

Example 92(2R,11aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-21)

Compound II-21 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁F₃N₂O₂×TFA. 363.1 (M+1).

Example 93(R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-22)

Compound II-22 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₁₉F₅N₂O₂×TFA. 427.1 (M+1).¹H NMR (DMSO) δ 8.22 (d, J=2.4 Hz, 1H), 7.84 (m, 5H), 7.18 (d, J=8.4 Hz,1H), 6.22 (tm, J=55.6 Hz, 1H), 4.53 (m, 1H), 4.27 (m, 1H), 3.97 (br,2H), 3.62 (m, 1H), 2.90-2.60 (m, 6H). ¹⁹F NMR (DMSO) δ −61.4 (s, 3F),−119.4 (dt, 55.6, 16.2 Hz, 2F).

Example 94(R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-23)

Compound II-23 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₂₁F₃N₂O₂×TFA. 391.1 (M+1).

Example 95(S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-24)

Compound II-24 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₁₉F₅N₂O₂×TFA. 427.1 (M+1).¹H NMR (DMSO) δ 8.22 (d, J=2.4 Hz, 1H), 7.84 (m, 5H), 7.18 (d, J=8.4 Hz,1H), 6.22 (tm, J=55.6 Hz, 1H), 4.53 (m, 1H), 4.27 (m, 1H), 3.97 (br,2H), 3.62 (m, 1H), 2.90-2.60 (m, 6H). ¹⁹F NMR (DMSO) δ −61.4 (s, 3F),−119.4 (dt, 55.6, 16.2 Hz, 2F).

Example 96(S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-25)

Compound II-25 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₂₁F₃N₂O₂×TFA. 391.1 (M+1).

Example 97(S)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-77)

Compound II-77 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₈F₃NO₂. 350.1 (M+1).

Example 98(R)-3-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-80)

Compound II-80 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₃H₁₉F₃N₂O₂×TFA. 413.1 (M+1).

Example 99(S)-3-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-81)

Compound II-81 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₃H₁₉F₃N₂O₂×TFA. 413.1 (M+1).

Example 1004-(1-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-82)

Compound II-82 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₂×TFA. 414.1 (M+1)

Example 101(R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-83)

Compound II-83 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₁₈F₆N₂O₂×TFA. 445.1 (M+1)

Example 102(R)-4-benzyl-2-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-85)

Compound II-85 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₄H₂₀F₃NO₂ 412.1 (M+1).

Example 103(S)-4-benzyl-2-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-86)

Compound II-86 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₄H₂₀F₃NO₂ 412.1 (M+1).

Example 104(S)-2-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-101)

Compound II-101 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₂. 414.1 (M+1)

Example 1052-(pyridin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone(Compound III-29)

Compound III-29 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₃H₁₉F₃N₂O₂. 413.1 (M+1).

Example 1062-(pyrimidin-2-yl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone(Compound III-30)

Compound III-30 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₂. 414.1 (M+1).

Example 1074-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyltrifluoromethanesulfonate (Compound II-171)

Compound II-171 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₁₆F₃N₃O₅S. 480.1 (M+1).

Example 108(R)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)(pyrimidin-2-yl)methanone(Compound III-38)

Compound III-38 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₃. 430.1 (M+1).

Example 109(S)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)(pyrimidin-2-yl)methanone(Compound III-39)

Compound III-39 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₈F₃N₃O₃. 430.1 (M+1).

Example 110Phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-4)

Compound III-4 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₃H₁₈F₃NO₃ as(M+H)⁺ 414.1.

Example 1114-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-150)

Compound II-150 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₃H₁₈F₃NO₃ as(M+H)⁺ 414.2.

Example 1124-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-151)

Compound was prepared according to the Examples disclosed herein usingthe appropriate starting materials. MS found for C₂₃H₁₉F₃N₂O₂ as (M+H)⁺413.2 ¹H NMR (400 MHz, dmso-d₆): δ: 8.54 (d, J=5.6 Hz, 1H), 7.96 (d,J=2.4 Hz, 1H), 7.80-7.76 (m, 2H); 7.67 (d, J=8.0 Hz, 1H), 7.42-7.28 (m,4H); 7.14 (d, J=8.4 Hz, 1H); 4.86 (s, 2H), 4.38-4.36 (m, 2H), 3.72-3.64(m, 4H).

Example 113(1-methylcyclopropyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-10)

Compound III-10 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₂₀F₃NO₃ as(M+H)⁺ 392.0.

Example 114(3,3-difluorocyclobutyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-11)

Compound III-11 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₁₈F₅NO₃ as(M+H)⁺ 428.1.

Example 115(1-methyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-12)

Compound III-12 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₁₈F₃N₃O₃ as(M+H)⁺ 418.1. ¹H NMR (400 MHz, dmso-d₆): δ: 8.03 (s, 1H), 7.73-7.41 (m,7H); 7.03 (d, J=8.0 Hz, 1H), 4.82 (s, 2H), 4.26 (m, 2H); 4.00 (m, 2H);383 (s, 3H).

Example 116(1H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-15)

Compound III-15 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₀H₁₆F₃N₃O₃ as(M+H)⁺ 404.1.

Example 117(1,5-dimethyl-1H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-58)

Compound III-58 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₂H₂₀F₃N₃O₃ as(M+H)⁺ 432.1

Example 118Pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-23)

Compound III-23 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₁₆F₃N₃O₃ as(M+H)⁺ 416.1.

Example 119Pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-24)

Compound III-24 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₁₆H₁₄F₃NO₂ as(M+H)⁺ 310.1. MS found for C₂₁H₁₆F₃N₃O₃ as (M+H)⁺ 416.1.

Example 1204-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-87)

Compound II-87 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₁₉N₃O₂ as(M+H)⁺ 346.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.90(d, J=2.4 Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H),7.40 (t, J=5.2 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H),4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.31 (s, 3H).

Example 1217-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-88)

Compound II-88 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₀H₁₆N₃O₂Cl as(M+H)⁺ 366.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.94(d, J=2.4 Hz, 1H), 7.79 (dd, J=2.4, 8.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H),7.49 (d, J=8.0 Hz, 2H), 7.40 (t, J=5.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H),4.97 (s, 2H), 4.51-4.49 (m, 2H), 3.77-3.74 (m, 2H).

Example 1227-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-89)

Compound II-89 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₃H₂₃N₃O₂ as(M+H)⁺ 374.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.90(d, J=2.4 Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H),7.41 (t, J=5.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.4 Hz, 1H),4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.91 (m, 1H); 1.22(d, J=7.2 Hz, 6H).

Example 1237-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-91)

Compound II-91 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₂H₂₁N₃O₂ as(M+H)⁺ 360.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.91(d, J=2.4 Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H),7.41 (t, J=5.2 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H),4.97 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.64 (q, J=7.6 Hz,2H); 1.20 (d, J=7.6 Hz, 3H).

Example 1247-(4-cyclopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-92)

Compound II-92 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₂H₂₁N₃O₂ as(M+H)⁺ 372.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.88(d, J=2.4 Hz, 1H), 7.74 (dd, J=2.4, 8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H),7.41 (t, J=5.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.4 Hz, 1H),4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 1.94-1.89 (m, 1H);0.97-0.93 (m, 2H); 0.70-0.66 (m, 2H).

Example 1257-(4-methoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-94)

Compound II-94 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₁₉N₃O₃ as(M+H)⁺ 362.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.78 (d, J=5.2 Hz, 2H), 7.86(d, J=2.4 Hz, 1H), 7.72 (dd, J=2.4, 8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H),7.41 (t, J=5.2 Hz, 1H), 7.10 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H),4.97 (s, 2H), 4.48-4.45 (m, 2H), 3.76 (s, 3H); 3.74-3.72 (m, 2H).

Example 1267-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-97)

Compound II-97 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₄H₂₅N₃O₃ as(M+H)⁺ 404.1. ¹H NMR (400 MHz, dmso-d₆): δ: 8.78 (d, J=5.2 Hz, 2H), 7.85(d, J=2.4 Hz, 1H), 7.72 (dd, J=2.4, 8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H),7.41 (t, J=5.2 Hz, 1H), 7.10 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.4 Hz, 1H),4.97 (s, 2H), 4.48-4.46 (m, 2H), 3.76-3.72 (m, 4H); 2.03-1.97 (m, 1H);0.97 (d, J=6.4 Hz, 6H).

Example 1277-(4-tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-98)

Compound II-98 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₄H₂₅N₃O₃ as(M+H)⁺ 404.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.78 (d, J=5.2 Hz, 2H), 7.91(d, J=2.4 Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H),7.46 (d, J=8.0 Hz, 2H); 7.41 (t, J=5.2 Hz, 1H); 7.11 (d, J=8.4 Hz, 1H),4.97 (s, 2H), 4.50-4.47 (m, 2H), 3.76-3.73 (m, 4H); 1.29 (s, 9H).

Example 1287-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-102)

Compound II-102 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₃H₂₁N₃O₃ as(M+H)⁺ 388.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.78 (d, J=5.2 Hz, 2H), 7.86(d, J=2.4 Hz, 1H), 7.72 (dd, J=2.4, 8.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H),7.41 (t, J=5.2 Hz, 1H); 7.46 (d, J=8.0 Hz, 2H), 7.11 (m, 3H), 4.97 (s,2H), 4.48-4.46 (m, 2H), 3.87-3.86 (m, 1H); 3.84-3.74 (m, 2H); 0.80-0.75(m, 2H); 0.67-0.65 (m, 2H).

Example 1297-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-117)

Compound II-117 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₀H₁₅N₃O₂FCl as(M+H)⁺ 384.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.87(d, J=2.4 Hz, 1H), 7.66 (dd, J=2.4, 8.8 Hz, 1H), 7.57-7.51 (m, 2H);7.41-7.35 (m, 2H); 7.16 (d, J=8.0 Hz, 1H), 4.97 (s, 2H), 4.54-4.52 (m,2H), 3.79-3.76 (m, 2H).

Example 130pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-1)

To a solution of7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(660 mgs, 2.0 mmol) in THF (6 mL), 1.0M Borane in THF (6.0 mL, 6.0 mmol)was added and the mixture was heated at 70° C. After 16 h, the mixturewas cooled to rt and Methanol (22 mL) and 6.0M HCl (22 mL) was added andstirred at rt for 2 h. The reaction mixture was then concentrated andthe solids formed were filtered and washed with ether and dried to give7-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepineas HCl salt. The above compound (100 mgs, 0.29 mmol),pyrimidine-2-carboxylic acid (47 mgs, 0.38 mmol), HATU (143 mgs, 0.38mmol), in DMF (1 mL) was added NMM (0.1 mL, 0.86 mmol) and stirred at60° C. for 30 min. The reaction mixture was then diluted with EtOAc andwashed with NaHCO₃, brine and dried (MgS(O)₄). The mixture was thefiltered, concentrated and chromatographed (SiO₂, 50% EtOAc/DCM) toprovide the title compound.

MS found for C₂₁H₁₆F₃N₃O₃ as (M+H)⁺ 415.9. ¹H NMR (400 MHz, dmso-d₆):mixture of rotomers (˜2:1): ¹H-NMR (DMSO) of the major rotomer: δ 8.86(d, J=5.2 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.75 (m, 1H); 7.69-7.54 (m,2H); 7.47-7.40 (m, 2H); 7.11 (d, J=8.0 Hz, 1H); 4.85 (s, 2H); 4.25-4.03(m, 4H); 3.58-3.56 (m, 2H).

Example 1317-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-3)

Compound V-3 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₀H₂₁N₃O₂ as(M+H)⁺ 336.1.

Example 1327-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-5)

Compound V-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₁H₂₃N₃O₂ as(M+H)⁺ 350.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.76 (d, J=5.2 Hz, 2H), 7.65(d, J=2.4 Hz, 1H), 7.53 (dd, J=2.4, 8.4 Hz, 1H), 7.42-7.39 (m, 1H); 6.98(d, J=84 Hz, 1H); 6.08 (m, 1H); 4.94 (s, 2H), 4.44-4.42 (m, 2H),3.69-3.67 (m, 2H); 2.36-2.23 (m, 4H); 1.81-1.66 (m, 5H); 1.31-1.26 (m,1H).

Example 1337-(4-ethylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-6)

Compound V-6 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS found for C₂₂H₂₅N₃O₂ as(M+H)⁺ 364.1 ¹H NMR (400 MHz, dmso-d₆): δ: 8.77 (d, J=5.2 Hz, 2H), 7.65(d, J=2.4 Hz, 1H), 7.52 (dd, J=2.4, 8.4 Hz, 1H), 7.42-7.38 (m, 1H); 6.98(d, J=8.4 Hz, 1H); 6.09 (m, 1H); 4.94 (s, 2H), 4.44-4.42 (m, 2H),3.70-3.67 (m, 2H); 2.36-2.25 (m, 3H); 1.84-1.77 (m, 2H); 1.32-1.26 (m,4H); 0.91-0.88 (m, 3H).

Example 134(R)-7-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-8)

The racemic7-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-onewas separted using chiral preparative HPLC to give pure enantiomers ofCompound V-8 and Compound V-9.

R-enantiomer: MS found for C₂₁H₂₃N₃O₂ as (M+H)⁺ 350.1

Example 135(S)-7-(4-methylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-9)

Compound V-9 was prepared according to the Example above. S-enantiomer:MS found for C₂₁H₂₃N₃O₂ as (M+H)⁺ 350.1

Example 1363-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-142)

Synthesis of 6-(4-(trifluoromethoxy)phenyl)chroman-4-one. See previousSuzuki reaction conditions. m/z=309.0

Synthesis of3-(pyridin-2-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)chroman-4-one. Asolution of 400 mg 6-(4-(trifluoromethoxy)phenyl)chroman-4-one (1.3mmol, 1.0 eq), 150 μL 2-pyridine carboxaldehyde (1.6 mmol, 1.2 eq) and130 μL pyrrolidine (1.6 mmol, 1.2 eq) in 10 mL ethanol was refluxed 3 h.The reaction was concentrated and purified on silica gel column elutingwith EA:Hex. 160 mg of a yellow solid was collected. m/z=398.0

Synthesis of3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)chroman-4-one. Asolution of 150 mg3-(pyridin-2-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)chroman-4-one(0.38 mmol) in 20 mL EtOH with catalytic Pd/C was stirred under 1 atm ofhydrogen gas for 16 h. The reaction was filtered through celite and thefiltrate concentrated. The filtrate was purified on silica gel columneluting with EA:Hex. 85 mg of an off-white solid was collected. m/z=400.

Synthesis of3-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.To a solution of 72 mg3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)chroman-4-one (0.18mmol) in 1 mL methylsulfonic acid 35 mg sodium azide (0.54 mmol) wasadded. After 1 h, reaction was diluted with 5 mL water and neutralizedwith addition of 1N NaOH solution. The precipitate was filter off toafford 65 mg off-white powder of product. m/z=415.0

Example 1377-(4-(cyclobutylmethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-144)

Compound II-144 was prepared according to example 25 using2-(4-(cyclobutylmethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS found for C₂₅H₂₅N₃O₃ as (M+H)⁺ 416.22 ¹H NMR (400 MHz, dmso-d₆):¹H-NMR (DMSO) δ: 8.78 (d, J=5.2 Hz, 2H), 7.86 (d, J=2.0 Hz, 1H), 7.72(dd, J=2.4-8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.41 (t, J=5.2 Hz, 1H),7.09 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.97 (s, 2H), 4.48 (t,J=4.4 Hz, 2H), 3.97 (d, J=6.8 Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 2.75-2.67(m, 1H), 2.09-2.03 (m, 2H), 1.94-1.79 (m, 4H).

Example 1384-(pyrimidin-2-ylmethyl)-7-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-24)

Compound VI-24 was prepared according to example 25 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)pyridine.

Example 1397-(2-methyl-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-145)

Compound II-145 was prepared according to example 25 using2-methyl-4-(trifluoromethyl)phenylboronic acid. MS found forC22H18F3N3O2 as (M+H)⁺ 414.32

Example 1407-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-146)

Compound II-146 was prepared according to example 25 using2-methyl-4-(trifluoromethoxy)phenylboronic acid. MS found forC22H18F3N303 as (M+H)⁺ 430.19 ¹H NMR (400 MHz, dmso-d₆): ¹H-NMR (DMSO)δ: 8.77 (d, J=5.2 Hz, 2H), 7.64 (d, J=2.4 Hz, 1H), 7.48 (dd, J=2.4-8.4Hz, 1H), 7.40 (t, J=4.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.8Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.52 (t, J=4.4 Hz, 2H),3.78 (t, J=4.4 Hz, 2H), 2.25 (s, 3H).

Example 1417-(4-(difluoromethyl)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-157)

Compound II-157 was prepared according to example 25 using4-(difluoromethyl)phenylboronic acid. MS found for C22H18F2N202 as(M+H)⁺ 381.20 ¹H NMR (400 MHz, dmso-d₆): ¹H-NMR (DMSO) δ: 8.54 (s, 1H),8.02 (s, 1H), 7.85-7.80 (m, 4H), 7.65 (d, J=7.6 Hz, 2H), 7.38-7.31 (m,2H), 7.16 (d, J=8.0 Hz, 1H), 7.08 (t, J=55.6 Hz, 1H), 4.87 (s, 2H), 4.40(s, 2H), 3.71 (s, 2H).

Example 1424-(pyridin-2-ylmethyl)-7-(2-(trifluoromethyl)pyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-25)

Compound VI-25 was prepared according to example 25 using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine.

Example 1437-(4-chloro-3-fluorophenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-158)

Compound II-158 was prepared according to example 25 using4-chloro-3-fluorophenylboronic acid. MS found for C21H16ClFN2O2 as(M+H)⁺ 383.17 ¹H NMR (400 MHz, dmso-d₆): ¹H-NMR (DMSO) δ: 8.60 (d, J=4.8Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.79 (dd,J=2.4-8.4 Hz, 1H), 7.69 (dd, J=2.0-10.8 Hz, 1H), 7.61-7.47 (m, 4H), 7.09(d, J=8.4 Hz, 1H), 4.90 (s, 2H), 4.36 (t, J=4.8 Hz, 2H), 3.69 (t, J=4.8Hz, 2H).

Example 1447-(4-(difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-159)

Compound II-159 was prepared according to example 25 using2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS found for C₂₂H₁₈F₂N₂O₃ as (M+H)⁺ 397.22.

Example 1454-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-26)

Compound VI-26 was prepared according to example 25 using2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine.MS found for C21H16F3N3O2 as (M+H)⁺ 400.21.

Example 1467-(1-methyl-1H-pyrazol-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-27)

Compound VI-27 was prepared according to example 25 using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Example 1477-(1-isopropyl-1H-pyrazol-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-28)

Compound VI-28 was prepared according to example 25 using1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Example 1487-(1-methyl-1H-pyrazol-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-29)

Compound VI-29 was prepared according to example 25 using1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Example 1497-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-30)

Compound VI-30 was prepared according to example 25 using2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole. MSfound for C21H21N3O2S as (M+H)⁺ 380.20 ¹H NMR (400 MHz, dmso-d₆): ¹H-NMR(DMSO) δ: 8.53 (d, J=4.8 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.01 (dd,J=2.0-8.8 Hz, 1H), 7.94 (s, 1H), 7.78 (t, J=7.2 Hz, 1H), 7.36-7.28 (m,2H), 7.09 (d, J=8.0 Hz, 1H), 4.85 (s, 2H), 4.36 (t, J=4.4 Hz, 2H), 3.66(t, J=4.8 Hz, 2H), 1.36 (d, J=6.8 Hz, 6H).

Example 1504-(pyrimidin-2-ylmethyl)-7-(2,3,4-trifluorophenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-162)

Compound II-162 was prepared according to example 25 using2,3,4-trifluorophenylboronic acid. MS found for C20H14F3N3O2 as (M+H)⁺386.14.

Example 1517-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-163)

Compound II-163 was prepared according to example 25 using3,4-difluorophenylboronic acid. MS found for C20H15F2N3O2 as (M+H)⁺368.15.

Example 1524-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-31)

Compound VI-31 was prepared according to example 29 using2-bromo-5-(trifluoromethyl)thiophene. MS found for C20H15F3N202S as(M+H)⁺ 405.16 ¹H NMR (400 MHz, dmso-d₆): ¹H-NMR (DMSO) δ: 8.53 (d, J=4.8Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.87-7.71 (m, 3H), 7.59 (d, J=3.2 Hz,1H), 7.37-7.28 (m, 2H), 7.13 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 4.40 (t,J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 2H).

Example 1537-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-32)

Compound VI-32 was prepared according to example 29 using2-bromo-5-cyclopropylthiophene. MS found for C22H20N2O2S as (M+H)⁺377.18 ¹H NMR (400 MHz, dmso-d₆): ¹H-NMR (DMSO) δ: 8.53 (d, J=4.8 Hz,1H), 7.81-7.76 (m, 2H), 7.68 (dd, J=2.4-8.0 Hz, 1H), 7.36-7.24 (m, 3H),7.04 (d, J=8.4 Hz, 1H), 6.80 (d, J=3.6 Hz, 1H), 4.84 (s, 2H), 4.34 (t,J=5.2 Hz, 2H), 3.66 (t, J=5.2 Hz, 2H), 2.14-2.10 (m, 1H), 1.02-0.97 (m,2H), 0.71-0.67 (m, 2H).

Example 1547-(2-methylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-33)

Compound VI-33 was prepared according to example 29 using4-bromo-2-methylthiazole.

Example 1554-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-8)

A mixture of 5-bromoisatoic anhydride (1 g, 4.13 mmol), N-benzylglycine(0.628 g, 4.13 mmol) and DMSO (3 mL) was heated in the microwave at 200°C. for one hour. After cooling, the mixture was diluted with water andthe precipitate was filtered off, washed with water and dried, giving4-benzyl-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.4 g,98%) as an off-white powder.

4-Benzyl-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.4 g,4.05 mmol) was combined with 4-(trifluoromethyl)phenylboronic acid (0.77g, 4.05 mmol), potassium carbonate (1 g) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (148 mg,0.202 mmol) in 5 mL DMF. Water (3 mL) was added and the mixture washeated under nitrogen atmosphere at 80° C. for three hours. Aftercooling the mixture was diluted with ethyl acetate, washed with waterand brine, dried with magnesium sulfate and evaporated. Purification bysilica-gel chromatography (20-100% ethyl acetate in hexane) followed byrecrystallization gave4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(1.25 g, 75%) as a white powder.

¹H-NMR (DMSO) δ: 10.61 (s, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.4Hz, 3H), 7.11 (d, J=8.4 Hz, 2H), 7.36-7.25 (m, 5H), 7.22 (d, J=8.4 Hz,1H), 4.79 (s, 2H), 3.92 (s, 2H). MS: 411 (MH⁺).

Example 1564-benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-11)

4-Benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(9.80 mg, 0.024 mmol) and K₂CO₃ (10 mg, 0.072 mmol, 3.0 equiv.) wereplaced in a 0.5-2 mL Smith process vial under a nitrogen atmosphere. Tothe vial were added DMF (0.5 mL) and iodomethane (2.25 μL, 0.036 mmol,d=2.28 g/cm³, 1.5 equiv) at room temperature. After heating, stirred, at60° C. for 2 hours, the reaction mixture was concentrated en vacuo. Theresulting crude mixture was diluted with acetonitrile (1 mL), filteredthrough a syringe filter and injected into a preparative HPLC to givedesired product(4-benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione,1.8 mg) as a yellow film.

¹H-NMR (400 MHz; CD₃CN) δ 8.16 (d, 1H, J=2 Hz), 7.93 (dd, 1H, J=8.4 Hz,2 Hz), 7.92 (d, 2H, J=7.8 Hz), 7.82 (d, 2H, J=7.8 Hz), 7.47 (d, 1H,J=8.4 Hz), 4.98 (d, 1H, J=15 Hz), 4.73 (d, 1H, J=15 Hz), 4.10 (d, 1H,J=15 Hz), 3.70 (d, 1H, J=15 Hz), 3.37 (s, 3H). ¹⁹F-NMR (400 MHz; CD₃CN)δ −63.96 (s, 3F). LCMS (EI: 70 eV) 447.1 (M++Na), 425.1 (M++1).

Example 157(S)-3-(2-hydroxyethyl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-1)

2-Amino-5-iodobenzoic acid (1.327 g, 5.05 mmol),4-trifluoromethoxyboronic acid (1.455 g, 7.07 mmol, 1.4 equiv.),Pd(dppf)Cl₂.CH₂Cl₂ (183.0 mg, 0.252 mmol, 5 mol %) and K₂CO₃ (1.604 g,11.61 mmol, 2.3 equiv.) were dissolved in a mixture ofH2O/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL Smith process vialequipped with a stir bar under a nitrogen atmosphere. The mixture washeated at 90° C. for 1 hour. After aqueous workup and removal ofvolatile solvents en vacuo, the mixture was purified by automatedsilica-gel column chromatography using an EtOAc/hexane gradient as theeluent. The purification gave the desired product(4-amino-4′-(trifluoromethoxy)biphenyl-3-carboxylic acid, 462.0 mg) as acolorless powder.

To a suspension of 4-amino-4′-(trifluoromethoxy)biphenyl-3-carboxylicacid (462.0 mg, 1.554 mmol) in CH₂Cl₂ (10 mL) in a round bottomed flaskwas added triethylamine (210 μL, 1.492 mmol, d=0.726 g/cm³, 0.96equiv.). Flask was charged with nitrogen, cooled to 0° C. and a solutionof triphosgene (148.0 mg, 0.497 mmol, 0.32 equiv.) in 2 mL DCM wasadded, followed by a solution of N,N-dimethyl-4-aminopyridine (30 mg,0.246 mmol, 25 mol %) in CH₂Cl₂ (2 mL). Reaction mixture was allowed tostir 2 hours, then quenched with a small portion of 1N HCl. Reactionmixture with resulting precipitate was filtered through a disposablefilter funnel and air-dried to give desired product(6-(4-(trifluoromethoxy)phenyl)-1H-benzo[d][1,3]oxazine-2,4-dione, 348.6mg) as a colorless solid.

6-(4-(Trifluoromethoxy)phenyl)-1H-benzo[d][1,3]oxazine-2,4-dione (348.6mg, 1.077 mmol) and K₂CO₃ (228 mg, 2.153 mmol, 2 equiv.) were placed ina 0.5-2 mL Smith process vial. To the vial was added DMF (3 mL) andiodomethane (101 μL, d=2.28, 1.615 mmol, 1.5 equiv.) at ambienttemperature. The mixture was stirred overnight at room temperature andthen filtered through a disposable filter funnel. Obtained filtrate wasdiluted with water to form precipitates, which were collected on adisposable filter funnel and allowed to air-dry to give desired product(1-methyl-6-(4-(trifluoromethoxy)phenyl)-1H-benzo[d][1,3]oxazine-2,4-dione,357.2 mg) as a colorless solid.

1-Methyl-6-(4-(trifluoromethoxy)phenyl)-1H-benzo[d][1,3]oxazine-2,4-dione(60 mg, 0.178 mmol) and L-homoserine (23.3 mg, 0.196 mmol, 1.1 equiv.)were added to a magnetically stirred 0.5-2 mL Smith process vialcontaining 0.75 mL glacial acetic acid. Reaction mixture was then heatedfor 2 hours at 130° C. Excess acetic acid was then removed en vacuo,residue was dissolved into a minimal amount of acetonitrile and purifiedby reverse-phase preparative HPLC to give the title compound (7.6 mg)following removal of solvent as a clear yellow film.

LCMS (EI: 70 eV) 459.1 (M++Na), 437.1 (M++1)

Example 1581-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-2)

6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione (5.0 g, 20.66 mmol),iodomethane: (1.94 mL, d=2.28, 4.4 g, 31.0 mmol, 1.5 equiv.) and Na₂CO₃(4.38 g, 41.3 mmol, 2 equiv.) were placed in a round bottomed flask. Tothe flask were added DMF (40 mL) at ambient temperature. The mixture wasstirred overnight at room temperature and then filtered through a glassfilter. Obtained filtrate was diluted with water to form precipitates.The precipitates were dissolved in EtOAc and the solution was dried overMgS(O)₄. The solvent was removed under reduced pressure. At this point,since the conversion was ˜50%, K₂CO₃ (14.3 g, 103.3 mmol, 5 equiv.) andiodomethane (2.58 mL, d=2.28, 41.3 mmol, 2.0 equiv.) were added to thesolution of the crude material in DMF. The mixture was heated at 30° C.so that the reaction can go to completion and then filtered through aglass filter. Obtained filtrate was diluted with water to formprecipitates. Formed precipitates were filtered through a glass filterto give the desired product(6-bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione). This was used forthe subsequent step without further purification.

6-Bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (5.29 g, 20.66 mmol)and glycine (1.7 g, 22.73 mmol, 1.1 equiv.) were dissolved in AcOH (100mL) in a round bottomed flask. The mixture was heated under refluxconditions for 2 hours. The mixture was purified by automated silica-gelcolumn chromatography using EtOAc/hexane gradient as the eluent. Thepurification give the desired product (7-bromo-1-methyl-3,4dihydro-1H-benzo[e][1,4]diazepine-2,5-dione, colorless powder, 446.7mg).

7-Bromo-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (446.7mg, 1.661 mmol), 4-trifluoromethoxyboronic acid (445.0 mg, 2.159 mmol,1.3 equiv.) Pd(dppf)Cl₂.CH₂Cl₂ (120.0 mg, 0.166 mmol, 10 mol %) andK₂CO₃ (482.0 mg, 3.49 mmol, 2.1 equiv.) were dissolved in a mixture ofH2O/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL round bottomedflask under a nitrogen atmosphere. The mixture was heated at 60° C. for64 hours. The mixture was purified by automated silica-gel columnchromatography using EtOAc/hexane gradient as the eluent. Evaporation ofsolvent en vacuo gave the title compound (415.0 mg) as a white powder.

LCMS (EI: 70 eV) 373.1 (M++Na), 351.1 (M++1)

Example 1591-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-3)

1-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(22.9 mg, 0.065 mmol) and NaH (15.6 mg, 0.650 mmol, 10.0 equiv.) wereplaced in a 0.5-2 mL Smith process vial. To the vial was added DMF (0.5mL) followed by 2-(chloromethyl)pyrimidine hydrochloride (53.9 mg, 0.327mmol, 5 equiv.) was added at room temperature. After stirring for 50min, reaction was quenched with AcOH. Resulting mixture was filtered andpurified via preparative reverse phase HPLC to give the title compound(2.2 mg) as a clear yellow film.

LCMS (EI: 70 eV) 443.1 (M++1)

Example 1601-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-4)

Compound X-4 was prepared according to the above example using theappropriate starting materials.

Example 1614-(4-(1H-pyrazol-1-yl)benzyl)-1-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-6)

Compound X-6 was prepared according to the above example using theappropriate starting materials.

Example 1621-(4-methoxybenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(Compound X-5)

7-Bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (510.0 mg, 2mmol) and Cs₂CO₃ (1.955 mg, 6 mmol, 3 equiv.) were placed in a roundbottomed flask. To the reaction vessel was added DMF (10 mL) and4-methoxybenzyl chloride (273 μL, 1.615 mmol, d=1.15 g/mL, 1 equiv.) atambient temperature. The mixture was stirred overnight at roomtemperature and then filtered through a disposable filter funnel.Resulting filtrate was concentrated en vacuo and purified by automatedsilica-gel column chromatography using an EtOAc/hexane gradient as theeluent to give the desired product(7-bromo-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione,378.3 mg) as a colorless solid.

7-Bromo-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (375.0mg, 1.007 mmol), 4-trifluoromethoxyboronic acid (270.0 mg, 1.31 mmol,1.3 equiv.) Pd(dppf)Cl₂.CH₂Cl₂ (72.9.0 mg, 0.101 mmol, 10 mol %) andK₂CO₃ (292.0 mg, 2.116 mmol, 2.1 equiv.) were dissolved in a mixture ofH₂O/toluene/i-PrOH (1.25 mL: 2.5 mL: 1.25 mL) in a 2-5 mL Smith processvial equipped with a stir bar under a nitrogen atmosphere. The mixturewas heated at 50° C. for 17 hours. After aqueous workup and removal ofvolatile solvents en vacuo, the mixture was purified by automatedsilica-gel column chromatography using an EtOAc/hexane gradient as theeluent. The purification gave the title compound (419 mg) as a colorlesspowder.

LCMS (EI: 70 eV) 479.1 (M++Na), 457.1 (M++1)

Example 1634-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-1)

To 2-bromo-5-fluoroisonicotinic acid (5 g, 22.72 mmol) benzyl aminoethanol (4.20 g, 27.27 mmol, 1.2 eq) was added in the presence of EDCI(5.2 g, 27.27 mmol, 1.2 eq) in dichloromethane (100 mL) and stirred atroom temperature for 4 h. The reaction mixture was diluted withdichloromethane, washed with water, brine, dried over sodium sulfate andconcentrated (5.0 g). The residue (5.0 g, 14.16 mmol) was cyclized bydissolving in DMF (20 mL), sodium hydride (1.2 g, 28 mmol) was added andstirred at room temperature for 2 h. The reaction mixture wasneutralized with dil. HCl and extracted with ethyl acetate, washed withwater, brine, dried over sodium sulfate and concentrated. Purified byflash chromatography furnished 4.4 g of the cyclized product.

The Suzuki coupling was performed under standard conditioned explainedin the other procedures using Pd(dppf)Cl₂. Mass (M+H)⁺ 415.1. CDCl₃:8.46 (S, 1H), 8.28 (S, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.42-7.32 (m, 5H),7.30 (d, J=8.0 Hz, 2H), 4.86 (s, 2H), 4.31 (t, J=4 Hz, 2H), 3.57 (t, J=4Hz, 2H)

Example 1644-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-9)

Alkylation of the amide was performed using sodium hydride following thestandard procedure to provide Compound XII-9. Mass (M+H)⁺ 379.0.

Example 1654-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-5)

Compound XII-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 417.0.

Example 1664-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-10)

Compound XII-10 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 446.1. CDCl₃: 8.55(s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.61 (d,J=2.8 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 4.55 (t, J=4 Hz,2H), 4.03 (s, 3H), 3.89 (t, J=4 Hz, 2 h).

Example 1674-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-8)

Compound XII-8 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 431.1. CDCl₃: 8.54(d, J=4.8 Hz, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 80.2 (d, J=8.8 Hz, 2H),7.29 (d, J=83.4 Hz, 2H), 7.08 (d, J=5.2 Hz, 1H), 5.05 (s, 2H), 4.72 (t,J=4.4 Hz, 2H), 3.83 (t, J=4.4 Hz, 2H), 2.52 (s, 3H).

Example 1684-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-11)

Compound XII-11 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 434.0. CDCl₃: 8.42(s, 1H), 8.30 (d, J=4.4 Hz, 1H), 8.23 (s, 1H), 7.96 (d, J=8.4 Hz, 2H),7.37 (t, J=8.4 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H),4.99 (s, 2H), 4.53 (t, J=4.4 Hz, 2H), 3.78 (t, J=4 Hz, 2H).

Example 1694-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one(Compound XII-14)

Compound XII-14 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 447.1.

Example 1704-benzyl-9-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-165)

Compound II-165 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 432.1. CDCl₃:7.80(s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.37 (dd, J1=2.4 Hz, J2=11.2 Hz, 1H),7.31 (d, J=4 Hz, 2H), 7.29-7.20 (m, 5H), 4.79 (s, 2H), 4.21 (t, J=5.2Hz, 2H), 3.47 (t, J=5.2 Hz, 2H).

Example 1714-benzyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-166)

Compound II-166 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 416.1. CDCl₃:7.87(s, 1H), 7.63 (s, 4H), 7.42 (dd, J1=1.6 Hz, J2=10.8 Hz, 1H), 7.32-7.24(m, 5H), 4.79 (s, 2H), 4.22 (t, J=5.2 Hz, 2H), 3.48 (t, J=5.2 Hz, 2H).

Example 1724-benzyl-8-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-167)

Compound II-167 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 432.1. CDCl₃:8.07(d, J=9.2 Hz, 1H), 7.58 (d, J=7.6 Hz, 2 h), 7.40-7.32 (m, 5H), 7.28 (d,J=8.4 Hz, 2H), 6.81 (d, J=11.2 Hz, 1H), 4.84 (s, 2H), 4.24 (t, J=4.8 Hz,2H), 3.54 (t, J=4.8 Hz, 2H).

Example 1734-benzyl-8-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-168)

Compound II-168 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 416.1. CDCl₃:8.11(d, J=9.2 Hz, 1H), 7.74-7.64 (m, 4H), 7.40-7.30 (m, 5H), 6.83 (d, J=11.6Hz, 1H), 4.85 (s, 2H), 4.26 (t, J=4.8 Hz, 2H), 3.56 (t, J=4.8 Hz, 2H).

Example 1744-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one(Compound XII-2)

Compound XII-2 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 415.1. CDCl₃: 8.09(d, J=8.4 Hz, 2H), 7.79 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H),7.44-7.32 (m, 5H), 7.30 (d, J=8 Hz, 2H), 4.91 (s, 2H), 4.18 (t, J=5.2Hz, 2H), (t, J=5.2 Hz, 2H).

Example 1754-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one(Compound XII-3)

Compound XII-3 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 399.1. CDCl₃: 8.18(d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.71 (d, J=8 Hz, 2H), 7.48(d, J=8 Hz, 1H), 7.46-7.30 (m, 5H), 4.91 (s, 2H), 4.20 (t, J=5.2 Hz,2H), 3.54 (t, J=5.2 Hz, 2H).

Example 1764-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one(Compound XII-6)

Compound XII-6 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 417.0.

Example 1774-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one(Compound XII-7)

Compound XII-7 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. Mass (M+H)⁺ 401.0.

Example 1782,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-174)

Step 1: To a solution of 2-aminoethanol (2.0 g, 30 mmol) in methanol (50mL) at 0° C., Boc₂O (6.0 g, 27 mmol) was added slowly and the reactionmixture was stirred at r.t. for 2 h. Concentrate the reaction mixture toremove methanol, the residue was dissolved in ethyl acetate, the organiclayer was washed with brine, dried over sodium sulfate and concentratedto get the Boc protected amino ethanol (5.0 g) and used directly for thenext reaction.

Step 2: To a solution of DABCO (5 g, 45 mmol) in toluene (50 mL),N-Boc-2-aminoethanol (5 g, 30 mmol) in toluene was added at roomtemperature. The reaction mixture was cooled to 0° C. andbenzenesulfonyl chloride (5.8 g, 33 mmol) was added slowly and stirredat room temperature for 2 h. Water was added to the reaction mixture,adjust the pH of the mixture to 2-3 by adding 6N HCl. The organic layerwas separated, washed with water, sodium bicarbonate, water and brine.Dried over sodium sulfate and concentrated to get an oily product (6.0g, 70% yield from two steps) which was used directly for the next step.

Step 3: To a solution of protected aminoethanol (6 g, 19.5 mmol) in DMF(20 mL) methyl 5-bromo-2-hydroxybenzoate (3 g, 13 mmol) was addedfollowed by potassium carbonate (3.58 g, 26 mmol) and heated the mixtureat 70° C. for 4 h. Solvent was distilled off, the residue was treatedwith ethyl acetate. The organic layer was washed with water, brine andconcentrated to give an oily product (4 g, 81%) and is used for the nextstep.

Step 4: To the above oily product in methanol (10 mL) at roomtemperature HCl in methanol (2 ml in 10 mL) was added and heated at 70°C. for 2 h. Solvent was distilled off, the residue was treated withether, filtered the precipitate. The product obtained (2.5 g, 85%) isused for the cyclization step.

Step 5: To the above product (2.5 g, 9 mmol) in toluene (10 mL),triethylamine (4 ml, 36 mmol) was added and heated at 105° C. for 48 h,until the LC-MS no starting material. The reaction mixture was cooled,diluted with methylene chloride, separated the organic layer. Add waterto the organic layer and treated with 6N HCl, to adjust the pH 2. Theorganics were washed with water, brine and dried and concentrated. Theresidue was treated with dichloromethane and hexane and filtered theproduct 178-A (2.0 g, 90% yield).

Suzuki: To the bromide 178-A (2 g, 8.16 mmol, 1 eq), boronic acid 178-B(2.5 g, 12.2 mmol, 1.5 eq) and potassium carbonate (3.4 g, 24.48 mol, 3eq) in a round bottom flask, solvent (60 mL, toluene/isopropano/water:2/1/1) was added and stirred under nitrogen for 10 min. To the abovesolution the palladium catalyst Pd(dppf)Cl₂ (142 mg, 0.16 mmol, 0.02 eq)was added and heated at 85° C. for 2 h. The reaction mixture was dilutedwith ethyl acetate, separated the organic layer and filtered the organiclayer through a plug of celite and silica gel and concentrated. Columnpurification on silica gel using ethyl acetate/hexane as eluent provided178-C (2 g, 75% yield).

Alkylation: To a solution of 178-C (2 g, 6.12 mmol, 1 eq.) chloromethylpyrimidine 178-D (1.5 g, 9.17 mmol, 1.5 eq.) in DMF (10 mL), NaH (60%dispersion in oil) (600 mg, 25 mmol, 4 eq.) was slowly added at roomtemperature (slightly exothermic) and stirred at r.t. for 30 min. Thereaction mixture was treated with few drops of HCl, diluted the reactionmixture with ethyl acetate and treated with water. The organic layer wasseparated, washed with brine, dried and concentrated. Columnpurification on silica gel using ethyl acetate/hexane as eluent providedCompound II-174 (1.8 g, 70% yield). Mass (M+H)⁺ 420.1. CDCl₃:8.65 (d,J=5.2 Hz, 2H), 8.10 (s, 1H), 7.58-7.50 (m, 3H), 7.18 (d, J=8 Hz, 2H),7.14 (t, J=5.2 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.02 (s, 2H).

Example 1794-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-1)

4-((3-Methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-onewas prepared according to Example 25 using3-(bromomethyl)-3methyloxetane.

¹H-NMR (400 MHz, DMSO) 1.305 (s, 3H), 3.618-3.643 (m, 2H), 3.750 (s,2H), 4.183-4.198 (d, 2H, J=6 Hz), 4.346-4.322 (t, 2H, J, =4.8 Hz),4.563-4.577 (d, 2H, J, =5.6 Hz), 7.109-7.131 (d, 1H, J=8.8 Hz),7.413-7.433 (s, 2H, J=8 Hz), 7.752-7.786 (m, 3H), 7.878-7.883 (d, 1H,J=2 Hz), MS m/z 407.1 (MH⁺).

Example 1804-((3-((2-oxopyrrolidin-1-yl)methyl)oxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-108)

Compound 180-A and Compound II-108 was prepared according to Example 25using (3-(bromomethyl)oxetan-3-yl)methyl methanesulfonate.

Example 1814-(2-(2-oxopyrrolidin-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-116)

Compound II-116 was prepared according to Example 25 using1-(2-bromoethyl)pyrrolidin-2-one.

Example 1827-(2-methoxypyrimidin-5-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-7)

40-B (0.405 mmol), potassium carbonate (111 mmol) and Palladium chloridedppf catalyst (0.05 mmol) were combined in a mixture of toluene (3 mL),isopropanol (1 mL) and water (1 mL). The resulting suspension was heatedat 85 degrees for 2 hours. The reaction mixture was concentrated downand diluted with ethyl acetate and filtered through celite. The filtratewas washed with water. The organic layer was purified by prep HPLC andprep TLC to afford Compound VI-7.

Example 1831-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl)cyclopropanecarbonitrile(Compound II-109)

Compound II-109 was prepared according to the Examples disclosed hereinusing the appropriate starting materials.

Example 184N-(2-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)-5-(trifluoromethoxy)phenyl)acetamide(Compound II-111)

Compound II-111 was prepared according to the Examples disclosed hereinusing the appropriate starting materials.

Example 1857-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-14)

Compound VI-14 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 432.2 (M⁺).

Example 1864-(pyrimidin-2-ylmethyl)-7-(2-(2,2,2-trifluoroethylamino)pyrimidin-5-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-15)

Compound VI-15 was prepared according to the Examples disclosed hereinusing the appropriate starting materials.

Example 1877-(6-morpholinopyridin-3-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-16)

Compound VI-16 was prepared according to the Examples disclosed hereinusing the appropriate starting materials.

Example 188N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)ethanesulfonamide(Compound II-178)

II-74 (1.04 mmol) and NaH (3.13 mmol) was stirred in THF (6 mL) at 0degrees under nitrogen. Bromoacetonitrile was added dropwise. Theresulting reaction mixture was allowed to slowly warm up to roomtemperature over the period of 2 hours after which time the reactionmixture was quenched with water and then extracted with dichloromethane.The organic layer was purified by prep HPLC to afford 188-A.

188-A (0.635 mmol) was dissolved in a mixture of THF:MeOH (4:6 mL). Tothis was added cobalt chloride (2.49 mmol) and di-tert-butyldicarbonate(1.26 mmol) under nitrogen follow by addition of sodium borohydride(0.762 mmol). The resulting mixture was stirred at ambient temperatureovernight. The mixture was filtered through celite and washed with 9:1mixture of MeOH/H₂O. The filtrate was washed with saturated NaHCO₃ andthen extracted with ethyl acetate. The organic layer was dried overNa₂S(O)₄ and concentrated down to afford 188-B as an oil which was usedwithout further purifications to make 188-C.

188-B (200 mg) was combined with TFA (9 mL) and H₂O (1 mL) and stirredunder nitrogen for 2 hours. The reaction mixture was concentrated andused without further purifications to make Compound II-178.

A solution of 188-C (25 mg) in dicholoromethane (3 mL) was chilled in anice bath. To this was added triethylamine (0.1 mL) followed byethanesulfonyl chloride (0.05 mL). The reaction mixture was stirredunder cold conditions for 2 hours after which it was quenched withwater. The mixture was extracted with dichloromethane and purified byprep HPLC to afford Compound II-178. MS m/z 459.1 (M⁺).

Example 189N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)cyclopropanesulfonamide(Compound II-179)

Compound II-179 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 471.1 (M⁺).

Example 1904-fluoro-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide(Compound II-181)

Compound II-181 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 525.1 (M⁺).

Example 191N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)cyclopentanesulfonamide(Compound II-183)

Compound II-183 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 499.1 (M⁺).

Example 1921-methyl-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-1H-imidazole-2-sulfonamide(Compound II-184)

Compound II-184 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 511.1 (M⁺).

Example 193N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide(Compound II-177)

Compound II-177 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 507.1 (M⁺).

Example 194N-methyl-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide(Compound II-182)

Compound II-182 was prepared according to Example 25 using iodomethaneand Compound II-177.

Example 195N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-2-(pyrimidin-2-yl)acetamide(Compound II-185)

188-C (0.054 mmol) was dissolved in DMF (3 mL) follow by addition ofHATU and DIPEA. The resulting mixture was stirred at room temperaturefor 3 hours after which water was added and extracted withdichloromethane. The organic was purified by prep HPLC to affordCompound II-185.

Example 1964-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-68)

Compound II-68 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 446.1 (M+H).

Example 1974-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-67)

Compound II-67 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 415.1 (M+H).

Example 1984-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-65)

Compound II-65 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 450.0 (M+H).

Example 1994-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-64)

Compound II-64 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 418.1 (M+H).

Example 2004-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-46)

Compound II-46 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 338.1 (M+H).

Example 2014-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-45)

Compound II-45 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 450.1 (M+H).

Example 2024-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-41)

Compound II-41 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 482.1 (M+H).

Example 2037-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-16)

Compound II-16 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 483.1 (M+H).

Example 2044-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-11)

Compound II-11 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 382.1 (M+H).

Example 2054-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-6)

Compound II-6 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 388.1 (M+H).

Example 2064-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-5)

Compound II-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 472.1 (M+H).

Example 2077-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-104)

Compound II-104 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 350.1 (M+H).

Example 2087-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-106)

Compound II-106 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 448.1 (M+H).

Example 2094-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-107)

Compound II-107 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 430.1 (M+H).

Example 2107-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-115)

Compound II-115 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 561.1 (M+H).

Example 2114-((4-(pyrrolidin-1-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-125)

Compound II-125 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 485.1 (M+H).

Example 2124-((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-133)

Compound II-133 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 501.1 (M+H).

Example 2134-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-134)

Compound II-134 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.01 (d, 1H,J=2.4 Hz), 7.72-7.78 (m, 3H), 7.31-7.42 (m, 7H), 7.14 (d, 1H, J=8.0 Hz),4.85 (s, 2H), 4.25 (t, 2H, J=5.0 Hz), 3.60 (t, 2H, J=5.4 Hz); MS m/z414.1 (M+H).

Example 2144-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-137)

Compound II-137 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.41 (d, 1H,J=6.0 Hz), 8.01 (d, 1H, J=2.4 Hz), 7.77 (dd, 1H, J=8.8, 2.4 Hz), 7.71(d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.17 (d, 1H, J=8.0 Hz), 6.75(d, 1H, J=6.0 Hz), 4.97 (s, 2H), 4.58 (t, 2H, J=4.8 Hz), 3.95 (s, 3H),3.84 (t, 2H, J=5.2 Hz); MS m/z 446.1 (M+H).

Example 2154-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-138)

Compound II-138 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.59 (d, 1H,J=5.2 Hz), 8.02 (d, 1H, J=2.4 Hz), 7.76 (dd, 1H, J=8.4, 2.4 Hz), 7.71(d, 2H, J=8.4 Hz), 7.34 (d, 2H, J=8.0 Hz), 7.28 (d, 1H, J=5.2 Hz), 7.16(d, 1H, J=8.4 Hz), 5.03 (s, 2H), 4.59 (t, 2H, J=5.0 Hz), 3.83 (t, 2H,J=5.0 Hz)), 2.53 (s, 3H); MS m/z 430.1 (M+H).

Example 2164-((4-(piperidin-1-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-139)

Compound II-139 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.10 (d, 1H,J=7.2 Hz), 7.98 (d, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=8.4, 2.4 Hz), 7.71(d, 2H, J=9.2 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.01(d, 1H, J=7.6 Hz), 4.91 (s, 2H), 4.56 (t, 2H, J=5.0 Hz), 4.01 (br, 2H),3.88 (t, 2H, J=4.8 Hz)), 3.73 (br, 2H), 1.59-1.73 (m, 6H); MS m/z 499.2(M+H).

Example 2174-((4-(dimethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-140)

Compound II-140 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.14 (d, 1H,J=7.2 Hz), 7.99 (d, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=8.0, 2.4 Hz), 7.70(d, 2H, J=9.2 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.19 (d, 1H, J=8.4 Hz), 6.93(d, 1H, J=7.2 Hz), 4.93 (s, 2H), 4.59 (t, 2H, J=5.0 Hz), 3.90 (t, 2H,J=5.0 Hz)), 3.30 (s, 6H); MS m/z 459.1 (M+H).

Example 2184-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-141)

Compound II-141 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.08 (d, 1H,J=2.4 Hz), 7.79-7.84 (m, 3H), 7.74 (d, 2H, J=8.4 Hz), 7.29-7.41 (m, 5H),7.15 (d, 1H, J=8.4 Hz), 4.86 (s, 2H), 4.26 (t, 2H, J=5.2 Hz), 3.60 (t,2H, J=5.2 Hz); MS m/z 398.1 (M+H).

Example 2194-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-143)

Compound II-143 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.23 (d, 1H,J=5.6 Hz), 8.00 (d, 1H, J=2.8 Hz), 7.92 (d, 1H, J=8.4 Hz), 7.77 (dd, 1H,J=8.4, 2.4 Hz), 7.68-7.71 (m, 3H), 7.34 (d, 2H, J=8.0 Hz), 7.15 (d, 1H,J=8.8 Hz), 5.03 (s, 2H), 4.45 (t, 2H, J=4.8 Hz), 4.05 (s, 3H), 3.82 (t,2H, J=5.0 Hz); MS m/z 445.1 (M+H).

Example 2204-((1-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-147)

Compound II-147 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.01 (dd, 2H,J=9.4, 2.6 Hz), 7.76 (dd, 1H, J=8.2, 2.6 Hz), 7.72 (d, 2H, J=8.8 Hz),7.73-7.76 (m, 2H), 7.13 (d, 1H, J=8.4 Hz), 6.54 (d, 1H, J=2.4 Hz), 4.88(s, 2H), 4.35 (t, 2H, J=5.0 Hz), 3.69 (t, 2H, J=5.0 Hz); MS m/z 454.0(M+H).

Example 2217-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-148)

Compound II-148 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 494.0 (M+Na).

Example 2224-((1-cyclopentyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-152)

Compound II-152 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 472.1 (M+H).

Example 2234-((1-ethyl-1H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-153)

Compound II-153 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 7.99 (d, 1H,J=2.4 Hz), 7.71-7.76 (m, 3H), 7.61 (d, 1H, J=2.4 Hz), 7.35 (d, 2H, J=8.0Hz), 7.12 (d, 1H, J=8.4 Hz), 6.31 (d, 1H, J=2.4 Hz), 4.82 (s, 2H), 4.29(t, 2H, J=5.0 Hz), 4.17 (q, 2H, J=7.2 Hz), 3.64 (t, 2H, J=7.4 Hz), 1.45(t, 3H, J=7.4 Hz); MS m/z 432.1 (M+H).

Example 2244-((1-methyl-1H-imidazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-154)

Compound II-154 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 418.1 (M+H).

Example 2254-((4-methyl-1H-pyrazol-1-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-155)

Compound II-155 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 7.98 (d, 1H,J=2.4 Hz), 7.76 (dd, 1H, J=8.2, 2.6 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.61(s, 1H), 7.34-7.37 (m, 3H), 7.11 (d, 1H, J=8.8 Hz), 5.83 (s, 2H), 4.21(t, 2H, J=5.0 Hz), 3.76 (t, 2H, J=5.0 Hz), 2.09 (s, 3H); MS m/z 418.1(M+H).

Example 2264-((4-chloro-1H-pyrazol-1-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-156)

Compound II-156 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 7.99 (d, 1H,J=2.4 Hz), 7.91 (s, 1H), 7.77 (dd, 1H, J=8.4, 2.4 Hz), 7.71 (d, 2H,J=8.8 Hz), 7.52 (s, 1H), 7.35 (d, 2H, J=8.0 Hz), 7.13 (d, 1H, J=8.8 Hz),5.85 (s, 2H), 4.29 (t, 2H, J=5.0 Hz), 3.81 (t, 2H, J=5.2 Hz); MS m/z438.0 (M+H).

Example 2274-((1-methyl-1H-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-160)

Compound II-160 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 7.98 (d, 1H,J=2.8 Hz), 7.67-7.76 (m, 4H), 7.53 (s, 1H), 7.35 (d, 2H, J=8.0 Hz), 7.12(d, 1H, J=8.0 Hz), 4.69 (s, 2H), 4.31 (t, 2H, J=5.2 Hz), 3.87 (s, 3H),3.62 (t, 2H, J=5.0 Hz); MS m/z 418.1 (M+H).

Example 2284-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-164)

Compound II-164 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.37 (d, 1H,J=4.8 Hz), 8.00 (d, 1H, J=2.4 Hz), 7.76 (dd, 1H, J=8.0, 2.4 Hz), 7.72(d, 2H, J=8.8 Hz), 7.61 (t, 1H, J=9.2 Hz), 7.38-7.42 (m, 1H), 7.34 (d,2H, J=8.0 Hz), 7.14 (d, 1H, J=8.0 Hz), 5.07 (s, 2H), 4.45 (t, 2H, J=4.8Hz), 3.78 (t, 2H, J=4.8 Hz); MS m/z 433.1 (M+H).

Example 2297-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-169)

Compound II-169 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.35 (d, 1H,J=5.2 Hz), 8.00 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.61 (t, 1H, J=9.2 Hz),7.51-7.55 (m, 2H), 7.38-7.46 (m, 2H), 7.14 (d, 1H, J=8.0 Hz), 5.07 (s,2H), 4.46 (t, 2H, J=4.8 Hz), 3.78 (t, 2H, J=4.8 Hz); MS m/z 401.1 (M+H).

Example 2307-(2-fluoro-4-(trifluoromethyl)phenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-170)

Compound II-170 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.37 (d, 1H,J=4.8 Hz), 7.99 (s, 1H), 7.70-7.74 (m, 2H), 7.53-7.63 (m, 3H), 7.38-7.42(m, 1H), 7.17 (d, 1H, J=8.4 Hz), 5.07 (s, 2H), 4.49 (t, 2H, J=5.0 Hz),3.80 (t, 2H, J=4.8 Hz); MS m/z 435.1 (M+H).

Example 2314-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-176)

Compound II-176 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.36 (d, 1H,J=4.4 Hz), 8.06 (s, 1H), 7.71-7.81 (m, 3H), 7.72 (d, 2H, J=8.0 Hz), 7.60(t, 1H, J=9.0 Hz), 7.37-7.41 (m, 1H), 7.15 (d, 1H, J=8.4 Hz), 5.06 (s,2H), 4.46 (t, 2H, J=5.0 Hz), 3.78 (t, 2H, J=4.8 Hz); MS m/z 417.1 (M+H).

Example 2324-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-1)

Compound XIII-1 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 431.1 (M+H).

Example 2334-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-2)

233-A (70 mg, 0.21 mmol), 4-(trifluoromethoxy)phenol (45 mg, 0.252mmol), K₃PO₄ (134 mg, 0.63 mmol), Pd(OAc)₂ (3%) anddi-tert-butyl(2′4′6′-triisopropylbiphenyl-2-yl)phosphine (6%) in toluene(3.5 mL) were put onto microwave at 140° C. for 20 min. The reactionmixture was diluted with EtOAC, filtered through ceilite and washed withEtOAc. The filtrate was concentrated and purified by HPLC followed byprep-TLC (EtOAc) to afford Compound XIII-2 (1.8 mg). MS m/z 432.1 (M+H).

Example 2344-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-3)

Compound XIII-3 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 415.1 (M+H).

Example 2354-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-4)

235-A (70 mg, 0.21 mmol), 4-(trifluoromethoxy)aniline (45 mg, 0.252mmol), NaO^(t)Bu (40 mg, 0.42 mmol), Pd₂(dba)₃ (3%) and (R)-BINAP (6%)in toluene (3.5 mL) were put onto microwave at 130° C. for 10 min. Thereaction mixture was diluted with EtOAC, filtered through ceilite andwashed with EtOAc. The filtrate was concentrated and purified by HPLC toafford Compound XIII-4 (22.8 mg).

¹H-NMR (CD₃OD) δ 8.66 (d, 1H, J=5.2 Hz), 8.23 (t, 1H, J=8.0 Hz), 7.78(d, 1H, J=8.0 Hz), 7.68 (t, 1H, J=6.4 Hz), 7.41 (s, 1H), 7.22-7.40 (m,1H), 7.06-7.13 (m, 4H), 7.01 (d, 1H, J=8.8 Hz), 5.04 (s, 2H), 4.33 (t,2H, J=5.0 Hz), 3.74 (t, 2H, J=5.4 Hz); MS m/z 430.1 (M+H).

Example 2364-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-6)

Compound XIII-6 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.52 (d, 1H,J=5.2 Hz), 7.84 (t, 1H, J=7.6 Hz), 7.44-7.50 (m, 4H), 7.29-7.36 (m, 2H),7.10 (d, 2H, J=8.0 Hz), 7.03 (d, 1H, J=8.8 Hz), 4.94 (s, 2H), 4.29 (t,2H, J=5.2 Hz), 3.68 (t, 2H, J=5.6 Hz); MS m/z 414.1 (M+H).

Example 2377-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-10)

Compound XIII-10 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 445.1 (M+H).

Example 2387-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-12)

Compound XIII-12 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 444.1 (M+H).

Example 2395-benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-6(5H)-one(Compound X-12)

239-A (0.100 g, 0.244 mmol), 2, 2-dimethoxyethanamine (1 mL, 9.3 mmol)were mixed together, the resulting mixture was stirred at 100° C. for 4hours. When the reaction was cooled down, Water was added dropwise untilprecipitation was finished. The precipitates were collected byfiltration and washed with water to afford 239-B (0.111 g, 92%), MS m/z:498 (M+H)⁺.

239-B (0.104 g, 0.209 mmol), PPTS (0.525 g, 2.09 mmol) were added toToluene (5 mL). The resulting mixture was stirred at 120° C. overnight,concentrated and purified by preparative HPLC to afford Compound X-12(0.013 g, 14%). MS m/z: 434 (MH⁺).

Example 240N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)pyrimidine-2-carboxamide(Compound II-192)

Compound II-192 was prepared according to Examples 188 and 195 disclosedherein using the appropriate starting materials. MS m/z 473.1 (M⁺).

Example 2417-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-36)

Compound VI-36 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (DMSO) δ 8.77 (d, 2H,J=5.2 Hz), 7.79 (d, 1H, J=2.4 Hz), 7.68 (dd, 1H, J=8.2, 2.6 Hz), 7.40(t, 1H, J=5.0 Hz), 7.22 (d, 1H, J=3.2 Hz), 7.04 (d, 1H, J=8.8 Hz),6.78-6.79 (m, 1H), 4.95 (s, 2H), 4.47 (t, 2H, J=5.0 Hz), 3.73 (t, 2H,J=5.0 Hz), 2.07-2.13 (m, 1H), 0.96-1.00 (m, 2H), 0.66-0.70 (m, 2H); MSm/z 378 (M+H).

Example 2424-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-37)

Compound VI-37 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (DMSO) δ 8.70 (d, 2H,J=5.2 Hz), 7.72 (d, 1H, J=2.4 Hz), 7.61 (dd, 1H, J=8.2, 2.6 Hz), 7.30(t, 1H, J=5.0 Hz), 7.12 (d, 1H, J=3.2 Hz), 7.01 (d, 1H, J=8.8 Hz),6.72-6.75 (m, 1H), 4.91 (s, 2H), 4.42 (t, 2H, J=5.0 Hz), 3.71 (t, 2H,J=5.0 Hz), 2.07-2.11 (m, 1H), 0.94-1.1 (m, 2H), 0.64-0.69 (m, 2H); MSm/z 406 (M+H).

Example 2434-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-8)

Compound VIII-8 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.74 (d, 2H,J=4.8 Hz), 7.51-7.54 (m, 3H), 7.33-7.37 (m, 3H), 7.26 (dd, 1H, J=8.2,2.2 Hz), 6.94 (d, 1H, J=8.0 Hz), 5.02 (s, 2H), 4.45 (t, 2H, J=5.2 Hz),3.72 (t, 2H, J=5.2 Hz), 2.91-3.00 (m, 4H); MS m/z 428.1 (M+H).

Example 2444-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-9)

Compound VIII-9 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.34 (d, 1H,J=5.2 Hz), 7.50-7.60 (m, 4H), 7.33-7.40 (m, 3H), 7.25 (dd, 1H, J=8.4,2.4 Hz), 6.92 (d, 1H, J=8.0 Hz), 5.01 (d, 2H, J=1.6 Hz), 4.32 (t, 2H,J=5.2 Hz), 3.66 (t, 2H, J=5.2 Hz), 2.90-3.00 (m, 4H); MS m/z 445.1(M+H).

Example 2457-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-193)

Compound II-193 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.77 (d, 2H,J=5.2 Hz), 7.97 (d, 1H, J=2.0 Hz), 7.73 (dd, 1H, J=8.8, 2.4 Hz), 7.61(dd, 2H, J=6.8, 2.0 Hz), 7.38 (t, 1H, J=4.8 Hz), 7.02-7.14 (m, 7H), 5.07(s, 2H), 4.56 (t, 2H, J=5.0 Hz), 3.82 (t, 2H, J=5.0 Hz); MS m/z 442.1(M+H).

Example 2467-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-194)

Compound II-194 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.77 (d, 2H,J=5.2 Hz), 7.97 (d, 1H, J=2.4 Hz), 7.74 (dd, 1H, J=8.6, 2.6 Hz), 7.61(dd, 2H, J=6.8, 2.4 Hz), 7.35-7.39 (m, 3H), 7.10-7.15 (m, 2H), 7.01-7.06(m, 4H), 5.07 (s, 2H), 4.56 (t, 2H, J=5.2 Hz), 3.82 (t, 2H, J=5.0 Hz);MS m/z 424.1 (M+H).

Example 2477-(3-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-195)

Compound II-195 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 8.76 (d, 2H,J=5.2 Hz), 7.96 (d, 1H, J=2.4 Hz), 7.71 (dd, 1H, J=8.2, 2.6 Hz),7.34-7.44 (m, 5H), 7.23 (t, 1H, J=2.0 Hz), 7.10-7.14 (m, 2H), 7.02-7.04(m, 2H), 6.93-6.96 (m, 1H), 5.06 (s, 2H), 4.56 (t, 2H, J=5.0 Hz), 3.81(t, 2H, J=5.2 Hz); MS m/z 424.1 (M+H).

Example 248(E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-10)

Compound VIII-10 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z 424.1 (M+H).

Example 2494-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-11)

Compound VIII-11 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. ¹H-NMR (CD₃OD) δ 7.53-7.54 (m,3H), 7.26-7.37 (m, 8H), 6.93 (d, 1H, J=8.0 Hz), 4.82 (s, 2H), 4.16 (t,2H, J=5.2 Hz), 3.49 (t, 2H, J=5.2 Hz), 2.95-3.02 (m, 4H); MS m/z 426.1(M+H).

Example 2504-(3-(azetidin-1-ylsulfonyl)propyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-191)

Compound 250-C was synthesized from Compound 250-A and sultone 250-Bfollowing general alkylation procedures. Compound 250-C (84 mg, 0.19mmol) was treated with thionyl chloride at 60° C. overnight. Theresulting mixture was concentrated to afford crude Compound 250-D whichwas treated with a solution of azetidine (26 μL, 2 eq) and triethylamine(250 μL) in DCM, the resulting mixture was stirred at room temperaturefor several hours, concentrated and purified with HPLC to affordCompound II-191 (42 mg). MS m/z: 485 (MH⁺).

Example 251N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propane-1-sulfonamide(Compound II-190)

Compound II-190 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. MS m/z: 485 (MH⁺)

The following compounds were prepared according to the Examplesdisclosed herein using the appropriate starting materials:

4-(2,2,2-trifluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-2) MS m/z 406.0 (M+H)

4-(2-(pyrrolidin-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-3) MS m/z 421.1 (M+H)

(2S,11aR)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-20) MS m/z: 363 (MH⁺)

(R)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-26) MS m/z: 363 (MH⁺)

(R)-tert-butyl6-oxo-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(6H)-carboxylate(Compound II-27) MS m/z: 463 (MH⁺)

(S)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-28) MS m/z: 363 (MH⁺)

(S)-tert-butyl6-oxo-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(6H)-carboxylate(Compound II-29) MS m/z: 463 (MH⁺)

(2R,11aR)-2-(pyrimidin-2-ylamino)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-30) MS m/z: 441 (MH⁺)

4-((1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-32) MS m/z 548.1 (M+H)

(2S,11aS)-2-(pyrimidin-2-ylamino)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-34) MS m/z: 441 (MH⁺)

7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-35) m/z: 480.1 (MH⁺)

(2R,11aR)-2-(diethylamino)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-36) MS m/z: 419 (MH⁺)

(2S,11aS)-2-(diethylamino)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-37) MS m/z: 419 (MH⁺)

(2R,11aR)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-38) MS m/z: 363 (MH⁺)

tert-butyl(2R,11aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11a-hexahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ylcarbamate(Compound II-39) MS m/z: 463 (MH⁺)

4-((5-(pyrimidin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-40) MS m/z 483.1 (M+H)

ethyl3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)benzoate(Compound II-43) m/z: 486.1 (MH⁺)

tert-butyl(2S,11aS)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11a-hexahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ylcarbamate(Compound II-52) MS m/z: 463 (MH⁺)

4-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-53) MS m/z 458.1 (M+H)

4-(4-(trifluoromethoxy)benzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-55) MS m/z 498.1 (M+H)

7-(4-(trifluoromethoxy)phenyl)-4-(4-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-56) MS m/z 482.1 (M+H)

(2R,11aS)-2-hydroxy-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-58) MS m/z: 364 (MH⁺)

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-59) MS m/z 348 (MH⁺)

(S)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a-tetrahydrobenzo[f]pyrrolo[2,1-c][1,4]oxazepin-5(1H)-one(Compound II-60) MS m/z: 348 (MH⁺)

8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydrobenzo[f][1,4]oxazino[3,4-c][1,4]oxazepin-6(1H)-one(Compound II-63) MS m/z: 364 (MH⁺)

2-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethoxy)pyrimidine-4-carbonitrile(Compound II-66) MS m/z 471.1 (M+H)

4-(2-hydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-71) MS m/z 368.1 (M+H)

(R)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-76) MS m/z 349 (MH⁺)

(R)-3-isopropyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-78) MS m/z: 442 (MH⁺)

(S)-3-isopropyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-79) MS m/z: 442 (MH⁺)

(S)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6(2H)-one(Compound II-84) m/z: 445 (MH⁺)

7-(4-morpholinophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-90) m/z: 417.2 (MH⁺)

7-(4-(methylsulfonyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-93) m/z: 410.0 (MH⁺)

(R)-4-(1-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-95) m/z: 414 (MH⁺)

(S)-4-(1-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-96) m/z: 414 (MH⁺)

7-(4-tert-butoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-99) m/z: 404.5 (MH⁺)

(R)-2-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-100) m/z: 414 (MH⁺)

tert-butyl4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenylcarbamate(Compound II-103) m/z: 447.1 (MH⁺)

N-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)phenyl)cyclopropanecarboxamide(Compound II-112) m/z: 415.2 (MH⁺)

4-((5-(pyridin-3-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-114) MS m/z 493.1 (M+H)

7-(4-(2-hydroxypropan-2-yl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-118) m/z: 390.2 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroacetyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-121) m/z: 428.2 (MH⁺)

4-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-1) MS m/z 416.0 (M+H)

4-(pyridin-2-ylmethyl)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-2) MS m/z 415.1 (M+H)

4-(pyridin-2-ylmethyl)-8-(3-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-3) MS m/z 399.1 (M+H)

4-(pyrimidin-2-ylmethyl)-8-(3-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-4) MS m/z 400.1 (M+H)

4-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-5) MS m/z 400.1 (M+H)

4-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-6) MS m/z 415.1 (M+H)

4-(pyrimidin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-7) MS m/z 416.1 (M+H)

4-(pyridin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound IV-8) MS m/z 399.1 (M+H)

7-(4-tert-butylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-1) m/z: 392.2 (MH⁺)

7-cyclopentenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-2) m/z: 322.1 (MH⁺)

7-(4,4-dimethylcyclohex-1-enyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-4) m/z: 364.2 (MH⁺)

7-(bicyclo[3.1.1]hept-2-en-3-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound V-7) m/z: 348.1 (MH⁺)

7-(2-oxo-1,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-1) m/z: 349.1 (MH⁺)

tert-butyl4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate(Compound VI-5) m/z: 436.9 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-6) MS m/z 431.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-8) MS m/z 401.1 (M+H)

7-(6-fluoropyridin-3-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-9) MS m/z 351.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-10) MS m/z 403.1 (M+H)

7-(2-(piperidin-1-yl)pyrimidin-5-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-11) MS m/z 417.1 (M+H)

7-(1-(cyclopropanecarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-17) m/z: 405.2 (MH⁺)

7-(pyrimidin-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-18) MS m/z 334.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-19) MS m/z 402.1 (M+H)

7-(cyclopropylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-1) m/z: 320.2 (MH⁺)

7-(3,3-dimethylbut-1-ynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-2) m/z: 336.1 (MH⁺)

7-((1-methyl-1H-imidazol-5-yl)ethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-3) m/z: 360.2 (MH⁺)

4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-135) m/z: 438.1 (MH⁺)

7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-136) m/z: 418.1 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-150) m/z: 459.2 (MH⁺)

4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound II-151) m/z: 458.2 (MH⁺)

cyclopropyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-8) m/z: 378 (MH⁺)

(1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-13) m/z: 404 (MH⁺)

(3,5-dimethyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-14) m/z: 432.2 (MH⁺)

(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-16) m/z: 486.1 (MH⁺)

(3-methyl-1H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone(Compound III-17) m/z: 418.2 (MH⁺)

1-morpholino-2-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone(Compound III-28) m/z: 421 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(pyrrolidin-1-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-34) MS m/z 325.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(pyrrolidin-1-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VI-35) MS m/z 324.1 (M+H)

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(Compound XII-12) MS m/z 415.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one(Compound XII-13) MS m/z 417.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-5) MS m/z 431.1 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)benzamide(Compound XIII-7) MS m/z 374.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-8) MS m/z 415.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)benzylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-9) MS m/z 445.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)benzylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound XIII-11) MS m/z 444.1 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)-4-(trifluoromethyl)benzamide(Compound XIII-13) MS m/z 442.1 (M+H)

7a-(7-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)tetrahydro-1H-pyrrolizin-3(2H)-one(Compound III-59) MS m/z 461.4 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)-4-(trifluoromethoxy)benzamide(Compound XIII-14) MS m/z 458.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(Compound VIII-7) MS m/z 427.4 (M+H)

Example 252

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

Example 253

A tablet Formula Is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets.

Example 254

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Example 255

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone  4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch  4.5 mg Magnesiumstearate  0.5 mg Talc  1.0 mg Total  120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Example 256

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Example 257

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Example 258

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Example 259

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/mL Mannitol, USP  50 mg/mLGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0mL Nitrogen Gas, NF q.s.

Example 260

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients and water thenadded q.s. 100 g.

Example 261

Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

The sustained release formulations of this disclosure are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate) andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma) and the like. These film-forming agents may optionally containcolorants, plasticizers and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Example 262

Activity testing is conducted in the Examples below using methodsdescribed herein and those well known in the art.

Sodium Current Screening Assays:

The late sodium current (Late INa) and peak sodium current (Peak INa)assays are performed on an automated electrophysiology platform, QPatch16× (Sophion Bioscience, Copenhagen, Denmark), which uses the whole cellpatch clamp technique to measure currents through the cell membrane ofup to 16 cells at a time. The assay uses an HEK293 (human embryonickidney) cell line heterologously expressing the wild-type human cardiacsodium channel, hNa_(v)1.5, purchased from Millipore (Billerica, Mass.).No beta subunits were coexpressed with the Na channel alpha subunit.Cells are maintained with standard tissue culture procedures and stablechannel expression is maintained with 400 μg/mL Geneticin in the culturemedium. Cells isolated for use on QPatch are incubated for 5 minutes inDetachin 1×(Genlantis, San Diego, USA) at 37° C. to ensure that 80-90%of the cells are single and not part of a cell cluster. Experiments arecarried out at 23-25° C.

For both the Late INa and Peak INa assays, series resistancecompensation is set to 100% and series resistance and whole-cellcompensation are performed automatically. Currents are digitized at 25kHz and low-pass filtered at 12 kHz and 10 kHz for the late and peak INaassays, respectively. Currents through open sodium channels areautomatically recorded and stored in the Sophion Bioscience Oracledatabase (Sophion Bioscience, Copenhagen, Denmark). Analysis isperformed using QPatch Assay and database software and data are compiledin Excel.

Compound stocks are routinely made by the Gilead Sample Bank in plasticvials to 10 mM in dimethyl sulfoxide (DMSO). In some cases, whencompounds are not soluble in DMSO, they are made in 100% ethanol. Stocksare sonicated as necessary. The extracellular solution for screeningLate INa is composed of: 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mMMgCl₂ and 5 mM HEPES with pH adjusted to 7.4 using NaOH. Theintracellular solution used to perfuse the inside of the cells for boththe Late INa and Peak INa assays contains: 120 mM CsF, 20 mM CsCl, 5 mMEGTA, 5 mM HEPES and pH adjusted to 7.4 with CsOH. Compounds are dilutedin extracellular solution to 1 μM in glass vials and then transferred toglass well plates before robotic addition to the cells. The 0 mM Naextracellular solution (0Na-ECF) used at the end of each experiment forthe Late INa and Peak INa assays to measure baseline current contains:140 mM N-methyl-D-glucamine; 4 mM KCl; 1.8 mM CaCl₂; 0.75 mM MgCl₂; 5 mMHEPES and pH was adjusted to 7.4 with HCl.

Late INa Screening Assay:

For the Late INa assay, sodium channels are activated every 10 seconds(0.1 Hz) by depolarizing the cell membrane to −20 mV for 250milliseconds (ms) from a holding potential of −120 mV. In response to a−20 mV voltage step, typical hNa_(v)1.5 sodium currents activate rapidlyto a peak negative current and then inactivate nearly completely within3-4 ms.

Compounds were tested to determine their activity in blocking the latesodium current. Late INa was generated by adding 10 μM Tefluthrin(pyrethroid) to the extracellular solution while recording Na currents.To confirm the block of late I_(Na) observed using the automatedscreening method, a second late I_(Na) enhancer (ATX-II) and the manualpatch clamp method were used. ATX-II and tefluthrin occupy distinct,non-overlapping binding sites and modify Na⁺ channel functiondifferently to increase late I_(Na). Compounds tested have been foundgenerally to inhibit the enhanced late I_(Na) caused by either lateI_(Na) enhancer. For the purposes of the screening, late INa is definedas the mean current between 225 ms and 250 ms after stepping to −20 mVto activate Na channels. After establishing the whole cell recordingconfiguration, late INa activator is added to each well 4 times over a16-17 minute period so that the late component of the Na current reachesa stable value. Compounds were then added (typically at 1 in thepresence of the late INa activator, with 3 additions over the course of7 or 8 minutes. Measurements were made at the end of exposure to thethird compound addition and values were normalized to the current levelwhen all Na⁺ was removed from the extracellular solution after twoadditions of 0Na-ECF.

Results are reported as percent block of late INa. When tested in theassay disclosed above with 10 μM Tefluthrin activating late INa, forexample Compounds 11-105 inhibited (or reduced) the late sodium currentby 45% (see Table 1 for additional compound data). The inhibition ofLate INa of the cardiac isoform hNa_(v) 1.5 support the use of thecompounds of this disclosure to treat atrial arrhythmias, ventriculararrhythmias, heart failure (including congestive heart failure,diastolic heart failure, systolic heart failure, acute heart failure),Prinzmetal's (variant) angina, stable angina, unstable angina, exerciseinduced angina, congestive heart disease, ischemia, recurrent ischemia,reperfusion injury, myocardial infarction, acute coronary syndrome,peripheral arterial disease, pulmonary hypertension and intermittentclaudication.

Peak INa Screening Assay:

Compounds were also evaluated for their effect in several other assays,including their effect on Peak INa. Good separation between theconcentrations of test compound to reduce late and peak I_(Na) isbeneficial to enable separation of the desired effect to reduce lateI_(Na) induced electrical and mechanical dysfunction from the undesiredeffect to reduce peak I_(Na), which can lead to slowing or block ofconduction of electrical excitation in the heart. It is contemplatedthat the compounds of Formula I avoid significant block of peak INa.Since the peak INa in the cells used herein can be very large,introducing artifacts in the recording, the concentration of Na⁺ in thebath can be reduced to 20 mM and a nonpermeant cation added tocompensate for the Na⁺ that was removed to maintain the osmolarity andionic strength of the solution (see solution details below). Analysis ofpeak INa generally requires correction for rundown before determiningthe % block of peak current by the tested compound.

A separate Peak INa screening assay was developed to allow assessment ofthe effect of compounds on peak INa at both low and high stimulationfrequencies in order to identify compounds that are highly selective forblock of late INa but do not block peak INa. A low stimulation frequencyof 0.1 Hz was used to determine the effect of the test compound when thechannel spent most of the time in the resting (closed) state andprovides information about Tonic Block (TB). A higher stimulationfrequency (3 Hz) was used to measure block of the channel when it spentmore time in the activated and inactivated states and provided a measureof Use-Dependent Block (UDB). Use-dependent block refers to theaccumulation of block with increased frequency of channel activation.Block of cardiac peak I_(Na) by compounds of this disclosure isincreased with an increase in the frequency of stimulation from 0.1 to1-5 Hz (frequencies encountered either in the normal heart or duringtachycardia). It is therefore expected that reduction of peak I_(Na) bycompounds of this disclosure will be greater at high heart rates, suchas those during tachyarrhythmias, than at normal heart rates. As aconsequence, compounds of this disclosure may reduce Na⁺ and Ca²⁺overload due to late INa and abnormal electrical activity and electricalconduction in myocardium that is arrhythmic, especially during ischemia.

The −100 mV holding potential and the 3 Hz stimulation frequency werechosen so that the benchmark compound would have a small but detectableeffect under experimental conditions, allowing for direct comparison ofnew compounds with the benchmark. The extracellular solution forscreening Peak INa is composed of: 20 mM NaCl, 120 mM N-methyl-Dglucamine, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgCl₂ and 5 mM HEPES with pHadjusted to 7.4 using HCl. The intracellular solution used for the PeakINa assay is the same as outlined for the Late INa assay (see above).

For the peak INa assay, Na⁺ channels were activated by depolarizing thecell membrane to 0 mV for 20 ms from a holding potential of −100 mV.After establishing the whole cell recording configuration, channels werestimulated to open with low frequency stimulation (0.1 Hz) for 7 minutesso that the recording can be monotered and the extent to which therecording has stabilized can be assessed. After this stabilizationperiod the stimulation frequency was increased to 3 Hz for 2 minutes andthen returned to 0.1 Hz. Since 3 Hz stimulation causes a small decreasein the peak current even in the absence of compound, this internalcontrol was used for each cell, when no compound is present, to correctthe results from 3 Hz stimulation when compound is present. Following 3Hz stimulation under control conditions, the cell is allowed to recoverfor 200 seconds before compound is added. The test compound tested at 1or 3 μM (depending on the % block of late INa at 1 μM) was added 3 timesat 60 second intervals, while stimulating the channels to open at 0.1 Hzto monitor the progression of TB. After the third compound addition, a320 second wait period was imposed to allow for equilibration before thesecond period of 3 Hz stimulation begins. TB was measured before thesecond period of 3 Hz stimulation. Both TB and UDB were analyzed byincorporating rundown correction for the peak INa and UDB as calculatedby compensating for the small use-dependent effect of the stimulationprotocol on peak INa in the absence of compound. Compound II-105exhibited peak INa TB of 9% and peak INa UDB of 11%, both measured at 1μM.

The above data demonstrates the selectivity of Compound II-105 to blocklate INa compared to peak INa (45% versus 9% for peak INa TB; and 45%versus 11% for peak INa UDB) and suggests that Compound II-105 shouldshow minimal to no effects on conduction through the heart (which isdriven by peak INa) at concentrations that effectively block late INa.

hERG Screening Assay:

Compounds were also tested for their effect to block the hERG K⁺channel. At least a 3-5-fold separation, preferably 10 fold separation,of IC₅₀ values for compounds to inhibit late I_(Na) (more potent) andhERG (less potent) indicates that a compound is unlikely to cause QTprolongation and/or proarrhythmic effects at concentrations needed toreduce late I_(Na).

Compounds were screened to test their activity in blocking the hERGpotassium channel at AVIVA Biosciences (San Deigo, Calif., USA). ThehERG channel is heterologously expressed in a CHO (Chinese HamsterOvary) cell line. Cells were maintained with standard tissue cultureprocedures and stable channel expression was maintained with 500 μg/mLG418 in the culture medium. Cells were harvested for testing on thePatchXpress 7000A automated patch clamp with Accumax (Innovative CellTechnologies, San Diego, Calif.) to isolate single cells.

The following solutions were used for electrophysiological recordings.The external solution contained: 2 mM CaCl₂; 2 mM MgCl₂; 4 mM KCl; 150mM NaCl; 10 mM Glucose; 10 mM HEPES (pH 7.4 with 1M NaOH; osmolarity,˜310 mOsm). The internal solution contained: 140 mM KCl, 10 mM MgCl₂, 6mM EGTA, 5 mM HEPES, 5 mM ATP (pH adjusted to 7.25 with KOH; osmolarity,˜295 mOsm).

hERG channels were activated when the voltage was first stepped to −50mV for 300 ms from the −80 mV holding potential and then stepped to +20mV for 5 seconds. At +20 mV the channels open and then largelyinactivate, so the currents are relatively small. Upon returning to −50mV from +20 mV, hERG currents transiently become much larger asinactivation is rapidly removed and then the channel closes. The firststep to −50 mV for 300 ms was used as a baseline for measuring the peakamplitude during the step to −50 mV after channel activation. The peaktail current at −50 mV was measured both under control conditions andafter addition of compound, each cell serving as its own control.

All compounds were prepared as 10 mM DMSO stocks in glass vials. Stocksolutions were mixed by vigorous vortexing and sonication for about 2minutes at room temperature. For testing, compounds were diluted inglass vials using an intermediate dilution step in pure DMSO and thenfurther diluted to working concentrations in external solution.Dilutions were prepared no longer than 20 minutes before use.

For the electrophysiological recordings, after achieving the whole-cellconfiguration, cells were monitored for 90 seconds to assess stabilityand washed with external solution for 66 seconds. The voltage protocoldescribed above was then applied to the cells every 12 seconds andthroughout the whole procedure. Only cells with stable recordingparameters and meeting specified health criteria were allowed to enterthe compound addition procedure.

External solution containing 0.1% DMSO (vehicle) was applied to thecells first to establish the control peak current amplitude. Afterallowing the current to stabilize for 3 to 5 minutes, 1 μM and then 10μM test compounds were applied. Each compound concentration was added 4times and cells were kept in test solution until the effect of thecompound reached steady state or for a maximum of 12 minutes. Afteraddition of test compound, a positive control (1 μM Cisapride) was addedand must block >95% of the current for the experiment to be consideredvalid. Washout in the external solution compartment was performed untilthe recovery of the current reached steady state. Data were analyzedusing DataXpress software and its associated SQL server database,Clampfit (Molecular Devices, Inc., Sunnyvale, USA) and Origin 7(Originlab Corp.) When tested in the assay disclosed above, CompoundII-105 inhibited (or reduced) the activity of the hERG potassium channelby <10% at 1 μM (see Table 1 for additional compound data).

Compounds were tested using the above described assay methods. Data areobtained by testing the listed compounds at 1 μM concentration in thelate and peak INa assays (and other concentrations as needed) and at 1μM and 10 μM for the hERG channel assay.

TABLE 1 Late I_(Na) Assay results Late I_(Na) Peak TB Peak UDB No. 1 μM1 μM 1 μM II-1 25 II-3 15 II-4 30 II-5 26 II-6 16 II-7 34 II-8 21 II-1043 9 2 II-11 23 II-12 21 II-13 18 II-14 47 7 6 II-15 48 8 8 II-16 19II-17 59 47 46 II-19 21 II-21 18 II-22 30 II-23 25 II-24 23 II-25 25II-31 51 9 8 II-33 46 10 13 II-35 25 II-39 16 II-41 17 II-42 34 II-43 23II-44 39 II-45 27 II-46 25 II-47 60 13 45 II-48 47 13 53 II-49 63 28 44II-50 48 5 19 II-51 20 II-54 51 13 20 II-57 55 50 41 II-59 15 II-61 41II-62 49 10 14 II-64 55 12 19 II-65 19 II-67 22 II-68 17 II-69 33 II-7037 II-71 12 II-72 60 22 34 II-73 42 II-74 12 II-75 68 45 59 II-77 21II-83 31 II-87 22 II-88 41 II-89 28 II-91 54 8 11 II-92 34 II-95 19II-97 36 II-98 39 II-102 21 II-104 21 II-105 45 9 11 II-106 18 II-107 18II-110 35 II-113 27 II-115 21 II-117 37 II-122 19 II-123 21 II-124 17II-129 33 II-133 23 II-134 69 38 34 II-135 32 II-136 30 II-137 54 28 26II-138 47 16 23 II-139 31 II-140 32 II-141 73 40 40 II-142 19 II-143 65II-144 68 34 41 II-145 19 II-146 36 II-147 54 13 6 II-148 17 II-150 27II-151 51 13 14 II-152 23 II-153 56 15 13 II-154 25 II-155 38 13 11II-156 48 23 13 II-157 43 13 16 II-158 58 34 26 II-159 28 II-160 48II-162 20 II-163 28 II-164 75 II-165 56 15 30 II-166 53 20 34 II-167 5620 25 II-168 44 36 47 II-169 65 23 23 II-170 66 36 31 II-171 24 II-17233 II-174 48 7 18 II-175 53 21 16 II-176 68 45 44 II-177 22 II-178 19II-179 21 II-186 55 20 30 II-187 62 9 21 II-189 53 23 28 II-190 18II-191 25 II-192 15 II-193 70 II-194 63 II-195 66 III-1 33 III-4 35III-10 29 III-11 20 III-12 39 10 17 III-15 50 19 18 III-23 26 III-24 17III-29 48 11 14 III-30 16 III-32 22 III-33 37 III-37 41 III-38 28 III-4022 III-50 24 III-58 26 IV-4 14 V-1 24 V-3 23 V-5 49 5 5 VI-4 36 VI-11 19VI-26 28 VI-30 40 VI-31 61 50 42 VI-32 66 28 26 VI-36 47 VI-37 48 VIII-461 12 19 VIII-5 32 VIII-6 38 VIII-7 59 VIII-8 47 VIII-9 50 VIII-10 25VIII-11 42 IX-2 22 IX-3 27 X-8 50 6 10 X-11 48 17 20 X-12 26 XII-1 53 2521 XII-2 57 45 64 XII-3 44 51 79 XII-5 25 XII-8 36 XII-9 22 XII-10 45 1320 XII-11 55 25 24 XII-14 26 XIII-1 16 XIII-2 19 XIII-3 17 XIII-4 51 8 9XIII-6 60 8 8 XIII-10 22

The assay results shown in the above table establishes that compoundstested showed activity as modulators of late sodium current, for exampleby inhibiting (or reducing) the late sodium current.

In some embodiments the effects of a compound of Formula I are specificfor the late sodium current and show little or no activity with respectto one or more other ion channels. Thus, in some embodiments, a compoundhaving an activity of reducing late sodium current will also exhibitlittle or no activity with regard to the peak sodium current. Inparticular embodiments, a compound having an activity of reducing latesodium current will also exhibit little or no activity with regard tothe hERG potassium channel.

Table 2 is a summary comparing compound II-73 and ranolazine ability toblock late and peak hNa_(v) 1.5 Na⁺ current and hERG K⁺ current. Thedata in Table 2 were obtained in similar but not necessarlycontemporaneous experiments.

TABLE 2 IC₅₀ Ratio (fold) IC₅₀ μM Peak INa/ hERG/ Late INa Peak INa hERGLate INa Late INa II-73 0.6 ± 0.1 52 ± 5  5.7 ± 0.6 87 10 Ranolazine 6.7± 1.4 428 ± 33 13.4 ± 0.5 64 2

The above data suggests that the compound of Example II-73 exhibitscomparable or improved properties with respect to the tested parameters.

L-Type Ca2+ Channel Assay—ChanTest:

Selected compounds were screened for block of the cardiac L-type Ca²⁺channel (hCav1.2, encoded by the human CACNA1C gene and coexpressed withthe beta 2 subunit, encoded by the human CACNB2 gene and alpha2delta1,encoded by the CACNA2D1 gene). The Ca²⁺ channel is heterologouslyexpressed in a CHO (Chinese Hamster Ovary) cell line. Cells aremaintained following standard tissue culture procedures and stablechannel expression is maintained with appropriate selection antibioticsin the culture medium. Cells are harvested for testing on thePatchXpress automated patch clamp (Model 7000A, Molecular Devices,Sunnyvale, Calif.) by washing twice with Hank's Balanced Salt Solution,treating the cells with trypsin and re-suspending cells in culturemedium (4-6×10⁶ cells in 20 mL). Cells in suspension are allowed torecover for 10 minutes in a tissue culture incubator set at 37° C. in ahumidified 95% air, 5% CO₂ atmosphere.

The following solutions are used for electrophysiological recordings.The external solution contains (mM): 137 NaCl, 4 KCl, 1.8 CaCl₂, 1MgCl₂, 10 Glucose, 10 HEPES (pH 7.4 with NaOH). The internal solutioncontains (mM): 130 Cs Aspartate, 5 MgCl₂, 10 EGTA, 4 ATP, 0.5 GTP, 10HEPES, (pH adjusted to 7.2 with N-methyl-D-glucamine).

Vehicle is applied to naive cells (n≧2, where n=the number cells), for a5-10 minute exposure interval. Each solution exchange is performed inquadruplicate. At the end of each experiment, a saturating concentrationof nifedipine (10 μM) is added to block hCav1.2 current. Leak current isdigitally subtracted from the total membrane current record.

Test compound stock solutions are prepared by addition of dimethylsulfoxide (DMSO) and stored frozen. Each test compound DMSO stock issonicated (Model 2510/5510, Branson Ultrasonics, Danbury, Conn.), atambient room temperature for at least 20 minutes to facilitatedissolution. Test compound concentrations are prepared fresh daily bydiluting stock solutions into the standard extracellular physiologicalsaline solution (see above). The maximum percent of DMSO added withcompound is 0.1%. All test compound and control solutions are placed ina glass-lined 96-well compound plate before loading on PatchXpress.

Two concentrations (1, 10 μM) of each test compound are applied at five(5) minute intervals via disposable polyethylene micropipette tips tonaïve cells (n≧2, where n=the number cells/concentration). Each testcompound concentration is added to the cell in quadruplicate. Totalduration of exposure to each test compound concentration is 5 minutes.

Onset and steady state block of hCav1.2 (α1C/β2/α2δ□ channels ismeasured using a stimulus voltage pattern consisting of a depolarizingtest pulse (duration, 200 ms; amplitude, 10 mV) at 10 s intervals from a−80 mV holding potential. Peak current is measured during a step to 10mV.

When tested in the assay disclosed above, Compound II-73 blocked thehCav1.2 late current by 14% and peak current by 32% at 1 μMconcentration. At 10 μM concentration the compound II-73 blocked thehCav1.2 late current by 47% and the peak current by 79%.

Example 263

Compounds of this disclosure that block cardiac late I_(Na) may alsomediate UDB of other Na⁺ channel isoforms including the major Na⁺channel isoforms in peripheral nervous system pain fibers, Na_(V)1.7 and1.8. Compounds of this disclosure that block these channels may also beuseful to decrease neuropathic pain.

In particular embodiments, a compound will exhibit a high selectivityfor the late sodium current modulatory activity as compared to theactivity in one or more other ion channels. The selectivity of acompound may be determined by determining the percentage reduction inlate sodium current due to the compound, as measured by the assaydescribed above. The percentage reduction in one other ion channelactivity, such as the hERG potassium channel, due to the compound isdetermined as described above. The selectivity is determined by takingthe ratio of (percentage reduction in late sodium current) to(percentage reduction in one other ion channel activity). The assaysconducted to measure activities in this regard should be performed asdescribed above, with the compound at a concentration of 10 μM (or atthe upper limit of solubility, if less). In particular embodiments, theselectivity of a compound of the disclosure will be at least 5:1, e.g.at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1,at least 12:1, at least 15:1, at least 20:1, or at least 25:1, whencomparing the percentage reduction in late sodium current versuspercentage reduction of one of the peak sodium current, the hERGpotassium channel current. Selectivity data can be calculated based onthe values provided in the Examples above.

Evidence supports a role for the tetrodotoxin-sensitive Na_(v)1.7 in thepathogenesis of pain. In this assay, using whole-cell patch-clamptechnique, the effects of compounds of the disclosure on hNa_(v)1.7(hNa_(v)1.7+β1 subunits) peak Na⁺ current (I_(Na)) are tested asdescribed previously (Rajamani et al, 2009). Cells are continuouslymaintained using MEM (Gibco-Invitrogen, Carlsbad, Calif.) supplementedwith 10% heat inactivated fetal bovine serum, 1%penicillin-streptomycin, 600 μg/mL geneticin (Gibco-Invitrogen), 2 μg/mLblastocydin (Calbiochem, NJ, USA), and are incubated at 37° C. in anatmosphere of 5% CO₂ in air. For recording hNav1.7 I_(Na), HEK293 cellsare superfused with an extracellular solution containing (in mM): 140NaCl, 3KCl, 10 HEPES, 10 glucose, 1 MgCl₂, 1 CaCl₂, pH 7.4 (with NaOH).Patch pipettes are filled with an internal solution containing (in mM):140 CsF, 10 NaCl, 1 EGTA, 10 HEPES, pH 7.3 (with CsOH).

Whole-cell I_(Na) are recorded as described previously (Rajamani et al,2009) using an Axopatch 200B amplifier (Molecular Devices, Sunnyvale,USA). Signals are filtered at 5 kHz and sampled at 20 kHz. Patchpipettes are formed using borosilicate glass (World PrecisionInstruments, Sarasota, USA) using a micropipette puller (DaganCorporation, Minneapolis, USA). The offset potential is zeroed beforethe pipette is attached to the cell and the voltages are not correctedfor the liquid junction potential. In all recordings, 75-80% of theseries resistance compensation will be achieved, thus yielding a maximumvoltage error of ˜5 mV and leak currents are cancelled by P/4subtraction. pCLAMP 10.0 software (Molecular Devices) will be used togenerate voltage clamp protocols and acquire data. The membranepotential is held at −100 or −120 mV and the cell dialyzed with thepipette solution for 5-7 minutes before current is recorded, to avoidtime-dependent shifts in Na⁺ channel gating within the first severalminutes after patch rupture. In all experiments, the temperature ofexperimental solutions will be maintained at 20±1° C. using a CL-100bipolar temperature controller (Warner Instruments, Hamden, USA).

Data are analyzed using Clampfit and Microcal Origin (MicroCal,Northampton, USA) software.

When tested in the assay disclosed above, Compound II-73 blocked thehNa_(v) 1.7 sodium channel isoform with IC₅₀ of 5.2 μM at a frequency of10 Hz. Compound II-73 blocked the hNa_(v) 1.8 sodium channel isoformwith a IC₅₀ of >10 μM at a 10 Hz frequency. At higher frequency of 25Hz, compound II-73 blocked both hNa_(v) 1.7 and hNa_(v) 1.8 isoformswith IC₅₀ of 1.1 and 1.5 μM respectively. The inhibition of eitherhNa_(v) 1.7 and hNa_(v) 1.8 isoforms or the inhibition of both channelswhen stimulated at these frequencies support the use of compounds ofthis disclosure to decrease neuropathic pain.

Example 264

Expression of Human Na_(V)1.1 cDNA

All experiments with human Na_(V)1.1 are conducted as described (Kahlig,et al., PNAS, 105: 9799-9804). Briefly, expression of hNav1.1 isachieved by transient transfection using Qiagen Superfect reagent (5.5μg of DNA is transfected at a plasmid mass ratio of 10:1:1 forα₁:β₁:β₂). The human β₁ and β₂ cDNAs are cloned into plasmids containingthe marker genes DsRed (DsRed-IRES2-hβ₁) or eGFP (eGFP-IRES2-hβ₂)flanking an internal ribosome entry site (IRES).

Electrophysiology

Whole-cell voltage-clamp recordings are used to measure the biophysicalproperties of WT and mutant Na_(V)1.1 channels, as described previously(Kahlig, 2008). For recording hNav1.1 I_(Na), HEK293 cells aresuperfused with solution containing (in mM): 145 NaCl, 4 KCl, 1.8 CaCl₂,1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of 7.35 and osmolarity of 310mOsmol/kg. The pipette solution contains (in mM): 110 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 with an osmolarity of 300mOsmol/kg. Cells are allowed to stabilize for 10 min after establishmentof the whole-cell configuration before current is measured. Seriesresistance is compensated 90% to assure that the command potential isreached within microseconds with a voltage error<2 mV. Leak currents aresubtracted by using an online P/4 procedure and all currents arelow-pass Bessel filtered at 5 kHz and digitized at 50 kHz.

For use-dependent studies, cells are stimulated with depolarizing pulsetrains (−10 mV, 5 ms, 300 pulses, 10 and 25 Hz) from a holding potentialof −120 mV. Currents are then normalized to the peak current recorded inresponse to the first pulse in each frequency train. For tonic blockstudies, peak and persistent (late) currents are evaluated in responseto a 200 ms depolarization to −10 mV (0.2 Hz) following digitalsubtraction of currents recorded in the presence and absence of 0.5 μMtetrodotoxin (TTX). The sodium current termed Late INa in the peripheryis commonly called persistent INa in the CNS. Persistent current iscalculated during the final 10 ms of the 200 ms step. Data analysis isperformed using Clampfit 9.2 (Axon Instruments, Union City, Calif.,U.S.A), Excel 2002 (Microsoft, Seattle, Wash., U.S.A.), and OriginPro7.0 (OriginLab, Northampton, Mass., U.S.A) software. Results arepresented as mean±SEM.

In Vitro Pharmacology

A stock solution of 10 mM compound of Formula I is prepared in 0.1 M HClor DMSO. A fresh dilution of the compound of Formula I in the bathsolution is prepared every experimental day and the pH is readjusted to7.35 as necessary. The final DMSO concentration was kept at 0.1% in allsolutions. Direct application of the perfusion solution to the clampedcell is achieved using the Perfusion Pencil system (Automate, Berkeley,Calif.). Direct cell perfusion is driven by gravity at a flow rate of350 μL/min using a 250 micron tip. This system sequesters the clampedcell within a perfusion stream and enables complete solution exchangewithin 1 second. The clamped cell is perfused continuously startingimmediately after establishing the whole-cell configuration. Controlcurrents are measured during control solution perfusion. Whereappropriate, concentration inhibition curves are fit with the Hillequation: I/I_(max)=1/[1+10^(log IC₅₀−I)*k], where IC₅₀ is theconcentration that produces half inhibition and k is the Hill slopefactor.

Solutions containing the compounds of the disclosure are perfused forthree minutes prior to current recordings to allow equilibrium (tonic)drug block. Tonic block of peak current is measured from thissteady-state condition. Use-dependent block of peak current is measuredduring pulse number 300 of the pulse train, (−10 mV, 5 ms, 300 pulses,10 Hz) from a holding potential of −120 mV. Two sequential pulse trainstimulations are averaged to obtain mean current traces for eachrecording condition.

In Vivo Pharmacology

Jugular vein cannulated male Sprague Dawley rats (250-350 g, CharlesRiver Laboratories, Hollister, Calif.) are used to study brainpenetration of the compounds of the disclosure in vivo. Animal use isapproved by the Institutional Animal Care and Use Committee, GileadSciences. Three rats per group are infused intravenously with thecompound of the disclosure in saline at 85.5 μg/kg/min. After 1, 2.5 or5 h the animals are sacrificed for plasma and brain collection, andconcentrations of the compound of the disclosure are measured by liquidchromatography coupled with tandem mass spectrometry (LC-MS/MS). Braintissue is homogenated in 1% 2N HCl acidified 5% sodium fluoride (finalhomogenate is diluted 3-fold). Plasma and brain homogenate samples (50μl) are precipitated along with deuterated D3-Formula I as an internalstandard, vortexed and centrifuged. The supernatant (50 μL) istransferred and diluted with water (450 μl) prior to injection (10 μl).High performance liquid chromatography was performed using a ShimadzuLC-10AD liquid chromatograph and a Luna C18(2), 3 μm, 20×2.0 mm columnwith a mobile phase consisting of water containing 0.1% formic acid(solution A) and acetonitrile (solution B) carried out under isocraticconditions (75% solution A, 25% solution B; flow rate 0.300 ml/min).Mass spectrometric analyses are performed using an API3000 massspectrometer (Applied Biosystems, Foster City, Calif.) operating inpositive ion mode with MRM transition 428.1>98. Brain-to-plasma ratiosare calculated for each sample as ng compound/g brain divided by ngcompound/ml plasma.

Example 265

Expression of Human Na_(V)1.2 cDNA

Wild-type (WT) cDNA stably transfected in Chinese hamster ovary (CHO)cells is used to record I_(Na). Unless otherwise noted, all reagents arepurchased from Sigma-Aldrich (St Louis, Mo., U.S.A.).

Electrophysiology

Whole-cell voltage-clamp recordings are used to measure the biophysicalproperties of WT. Briefly, the pipette solution consists of (in mM) 110CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 and osmolarityof 300 mOsmol/kg. The bath (control) solution contains in (mM): 145NaCl, 4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of7.35 and osmolarity of 310 mOsmol/kg. Cells are allowed to stabilize for10 min after establishment of the whole-cell configuration beforecurrent is measured. Series resistance is compensated 90% to assure thatthe command potential is reached within microseconds with a voltageerror<2 mV. Leak currents are subtracted by using an online P/4procedure and all currents are low-pass Bessel filtered at 5 kHz anddigitized at 50 kHz.

For clarity, representative ramp currents are low pass filtered off-lineat 50 Hz. Specific voltage-clamp protocols assessing channel activation,fast inactivation and availability during repetitive stimulation areused. Results are presented as mean±SEM.

Tonic block of peak current is measured using a step to −10 mV (20 ms)from a holding potential of −120 mV (0.2 Hz). Use-dependent block ofpeak current is measured during pulse number 300 of a pulse train (−10mV, 5 ms, 300 pulses, 10 Hz or 25 Hz) from a holding potential of −120mV. Two sequential pulse train stimulations are averaged to obtain meancurrent traces for each recording condition, which are then used foroffline subtraction and analysis.

For use-dependent studies, cells are stimulated with depolarizing pulsetrains (−10 mV, 5 ms, 300 pulses, 10 and 25 Hz) from a holding potentialof −120 mV. Currents are then normalized to the peak current recorded inresponse to the first pulse in each frequency train. For tonic blockstudies, peak current is evaluated in response to a 20 ms depolarizationto −10 mV (0.2 Hz). Data analysis is performed using Clampfit 9.2 (AxonInstruments, Union City, Calif., U.S.A), Excel 2002 (Microsoft, Seattle,Wash., U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, Mass., U.S.A)software. Results are presented as mean±SEM.

In Vitro Pharmacology

A stock solution of 10 mM compound of Formula I is prepared in 0.1 M HClor DMSO. A fresh dilution of the compound of Formula I in the bathsolution is prepared every experimental day and the pH is readjusted to7.35 as necessary. The final DMSO concentration was kept at 0.1% in allsolutions. Direct application of the perfusion solution to the clampedcell is achieved using the Perfusion Pencil system (Automate, Berkeley,Calif.). Direct cell perfusion is driven by gravity at a flow rate of350 μL/min using a 250 micron tip. This system sequesters the clampedcell within a perfusion stream and enables complete solution exchangewithin 1 second. The clamped cell is perfused continuously startingimmediately after establishing the whole-cell configuration. Controlcurrents are measured during control solution perfusion.

Solutions are perfused for three minutes prior to current recordings toallow equilibrium (tonic) drug block. Tonic block of peak currents ismeasured from this steady-state condition. Three sequential currenttraces are averaged to obtain a mean current for each recording. Themean current traces are utilized for offline analysis. Use-dependentblock of peak current is measured during pulse number 300 of the pulsetrain, (−10 mV, 5 ms, 300 pulses, 10 Hz) from a holding potential of−120 mV. Two sequential pulse train stimulations are averaged to obtainmean current traces for each recording condition, which are then usedfor offline subtraction and analysis Where appropriate, concentrationinhibition curves are fit with the Hill equation: I/I_(max)=1/[1+10^(logIC₅₀−I)*k], where IC₅₀ is the concentration that produces halfinhibition and k is the Hill slope factor.

Results

Using the above methods it may be demonstrated that the compounds of thedisclosure are selective for inhibiting cardiac Late Ina current withoutinhibiting peak and low frequency currents of brain isoforms NaV 1.1 and1.2. The compounds of the disclosure may inhibit the very high frequencyfiring of Na_(v)1.1 and Na_(v)1.2 or demonstrate voltage dependent blockof mutant Na_(V)1.1 and Na_(V)1.2 observed with epilepsy patients. Inaddition compounds of this disclosure may show activity for inhibitionof a panel of Na_(V)1.1 mutant channels associated with the epilepsy andheadache (migraine) syndromes GEFS+, SMEI and FHM3 suggesting theability of the compounds of the disclosure to preferentially block theabnormal increased persistent current carried by these mutant channels.disclosure

When tested in the assay disclosed above for hNa_(v) 1.1 and hNa_(v) 1.2sodium channel isoforms, Compound II-73 blocked the hNa_(v) 1.1 sodiumchannel isoform peak INa with IC₅₀ value of >100 μM at a frequency of 10Hz and the hNa_(v) 1.2 sodium channel isoform peak INa with IC₅₀ valueof >30 μM at the same frequency. At higher frequency of 25 Hz thecompound II-73 blocked both hNa_(v) 1.1 and hNa_(v) 1.2 isoforms withIC₅₀ of 3.4 μM and 10.1 μM respectively. The inhibition of eitherhNa_(v) 1.1 and hNa_(v) 1.2 isoforms or the inhibition of both channelswhen stimulated at these frequencies support the use of compounds ofthis disclosure to treat patients with epilepsy.

TABLE 3 Late I_(Na) Assay results Late NAV1.1* NAV1.2* RHEART No.I_(Na)* UDB-10HZ UDB-10HZ hERG MAPD90_ATX* II-7 34 0 13 −10 II-10 43 −49 II-14 47 16 19 II-17 59 <10 II-22 30 3 15 16 II-42 34 2 12 −27 II-4625 2 16 II-61 41 9 25 <10 −62 II-73 42 10 19 18 −56 II-75 68 35 52 II-8331 −2 10 21 II-88 41 −10 −1 26 −69 II-91 54 −9 −3 II-98 39 −1 −8 <10 −50II-105 45 −17 1 <10 II-110 35 −4 −2 26 II-117 37 −11 −18 <10 II-129 33 87 17 −49 II-138 47 21 40 II-143 65 29 44 II-156 48 −23 III-1 33 −1 −3<10 −47 V-5 49 −18 3 VIII-4 61 5 18 30 −25 VIII-6 38 6 20 <10 −49 X-8 50−12 −14 <10 XII-1 53 −1 −4 XII-8 36 11 11 −34 *% Inhibition at 1 uM

Example 266

Ischemia-Induced ST Segment Elevation in Anesthetized Rabbits

This study was undertaken to determine the anti-ischemic effects ofcompounds of the present disclosure in an in vivo rabbit model.

Methods:

Female New Zealand rabbits (3.0-4.0 kg) were purchased from WesternOregon Rabbitry. Animals were housed on a 12-h light and dark cycle andreceived standard laboratory chow and water. All experiments wereperformed in accordance with the Guide for the Care and Use ofLaboratory Animals published by The National Research Council and withthe experimental protocol approved by the Institutional Animal CareCommittee of Gilead Sciences, Inc.

Rabbits were anesthetized with ketamine (35 mg/kg) and xylazine (5mg/kg) intramuscular injection (im). A tracheotomy was performed and thetrachea was intubated with an endotracheal tube. The animal wasventilated with room air supplemented with oxygen using a pressurecontrol animal ventilator (Kent Scientific Corp., Torrington, Conn.) ata respiratory rate of 40 strokes/min and peak inspiration pressure of 10mmH₂O, which was adjusted to keep blood gases and pH within thephysiological range (iSTAT clinic analyzer, Heska Corp.; Waukesha,Wis.). The left femoral artery was cannulated for the measurement ofblood pressure (BP). Blood samples were also withdrawn from femoralartery. The right external jugular vein was cannulated for drug/vehicleadministration. Needle electrodes were inserted subcutaneously into thelimbs for recording of the surface electrocardiogram (ECG). The heartwas exposed via an incision in the 4^(th) intercostal space (4^(th)and/or 5^(th) ribs were cut for a clear surgical vision). The chest wasopened and a pericardial cradle was formed using 4 retractors. Acoronary artery occluder, comprised of a snare made of 5 cm PE-10 tubingwith a 6-0 Prolene polypropylene suture in it, was placed loosely aroundthe left anterior descending artery (LAD) at its origin. Two unipolarelectrodes, made with teflon coated silver wire attached to a smallpatch of filter paper, were attached on the surface of the ischemic andnormal regions of the left ventricle to record epicardialelectrocardiogram. Reference electrodes were placed in the open incisionof the neck. The body temperature of the animal was monitored via arectal thermometer and maintained at 37-40° C. by adjusting the surfacetemperature of the surgical table. Regional ischemia (15 min) wasinduced by ligating the LAD followed by 15 min of reperfusion caused byreleasing the ligation. The heart was excised at the end of theexperiment and the LAD was re-ligated. The ischemic area was visualizedby perfusing the heart with 1% Evans blue in saline and calculated as apercentage of total ventricular weight. Rabbits with ischemic area lessthan 10% or larger than 25% were excluded from the analysis. Animalswere randomly assigned to vehicle and test compound groups. Testcompounds was dissolved in 5% NMP, 30% PG, 45% PEG 400 and 20%de-ionized water (dH₂O). Test compound was given as an iv bolus at 0.1,0.2 and 0.4 mg/kg. After 30 min of dosing, the heart was subjected to 15min of ischemia followed by 15 min of reperfusion.

Results:

The compound of Example II-61 dose-dependently prevented theischemia-induced ST elevation. The area under curve (AUC) for the STsegment height was reduced (vs. control) by 38% and 88% at 0.28 and 0.52μM plasma concentration of compound of Example II-61. At the plasmaconcentration levels studied, compound of Example II-61 had nosignificant effect on blood pressure (BP), heart rate (HR) and ECGintervals prior to the ischemia. The data suggests the compound ofExample II-61 prevents ischemia-induced myocardial electricaldysfunction in a dose-dependent manner.

Similarly, compound of Example II-73 dose-dependently prevented theischemia-induced ST elevation. The area under curve (AUC) for the STsegment height was reduced (vs. control) by 55% and 93% at 0.25 and 0.5μM respective plasma concentration of compound of Example II-73. At theplasma concentration levels studied, compound of Example II-73 had nosignificant effect on blood pressure (BP), heart rate (HR) and ECGintervals prior to the ischemia. The data suggests the compound ofExample II-73 prevents ischemia-induced myocardial electricaldysfunction in a dose-dependent manner.

What is claimed is:
 1. A compound of formula:


2. A pharmaceutical composition comprising a compound of formula:

and a pharmaceutically acceptable carrier.